{"paper_id":"17db99e7-d1bb-4850-8f02-1c086758f455","body_text":"1 / 58\n1 Mechanisms of traditional Chinese medicine in \n2 modulating cardiac microvascular endothelial \n3 cells in various injury models: A comprehensive \n4 systematic review\n5\n6\n7 Huiwen Zhou1,2, Hongxu Liu1*, Xiang Li1,3*, Juju Shang1, Jiaping Chen1,2, Huiqi Zong1,4\n8\n9\n10\n11 1. Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, \n12 China\n13 2. Capital Medical University, Beijing, China\n14 3. Lhasa people’s hospital, Lhasa, China\n15 4. Beijing University of Chinese Medicine, Beijing, China\n16\n17\n18 *Corresponding author:\n19  E-mail: lhx_@263.net (HL); lixiang11897@bjzhongyi.com (XL)\n20\n21\n22\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 2 / 58\n23 Abstract\n24 Background\n25 The structural and functional failure of cardiac microvascular endothelial cells (CMECs) is \n26 a primary contributor to coronary microvascular dysfunction (CMD). Traditional Chinese \n27 medicine (TCM) has been identified as a potential therapeutic approach for preserving \n28 CMECs and mitigating CMD.\n29 Objective\n30 This systematic review aims to present the latest evidence on TCM intervention \n31 mechanisms in CMECs under diverse injury models.\n32 Methods\n33 This systematic review was performed following the parameters of the PRISMA statement \n34 (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). A comprehensive \n35 literature search was conducted using PubMed, Embase, Web of Science, Scopus, China \n36 National Knowledge Infrastructure and China Biology Medicine disc. Reference lists of \n37 selected articles were reviewed to identify relevant studies. The search was not limited by \n38 year and was conducted solely in English. Eligible studies comprised publications \n39 describing in vitro studies that presented the latest evidence on TCM intervention \n40 mechanisms in CMECs under diverse injury models.\n41 Results\n42 A total of 63 papers were included in this study. According to the cell processing approach, \n43 19 studies on ischemia or hypoxic injury models, 16 studies on Ischemia/reperfusion (I/R) \n44 or hypoxia/reoxygenation (H/R) injury models, 10 studies on inflammatory injury models, 5 \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 3 / 58\n45 studies on metabolic injury models, 3 studies on angiotensin II injury models, and 10 \n46 studies on other models. TCM exhibits structural and functional intervention capabilities in \n47 diverse damage conditions of CMECs. Its mechanism of action involves antioxidant, anti-\n48 apoptotic, anti-inflammatory effects, as well as regulation of energy metabolism through \n49 signaling pathways such as HIF-1α/VEGF, PI3K/AKT, MAPK, and NF-κB. \n50 Conclusions\n51 The CCM and its constituents modulate CMECs through multiple signaling pathways in \n52 response to various injury models, thereby conferring protection on the coronary \n53 microcirculation.\n54 Keywords\n55 Traditional Chinese medicine, Cardiovascular disease, Cardiac microvascular endothelial \n56 cells, Coronary microvascular dysfunction, Mechanisms\n57\n58 Abbreviations: 4-ACGC, 4-O-(2-O-acetyl-6-O-p-coumaroyl-β-D-glucopyranosyl)-p-\n59 coumaric acid; A, Allicin; ADM, Adriamycin; AJs, Adherens junctions; AKT, Protein kinase \n60 B; ALDH, Aldehyde dehydrogenase; AMPK, Adenosine 5′-monophosphate activated \n61 protein kinase; AND, Andrographolide; Ang Ⅱ, Angiotensin II; Angptl4, Angiopoietin-like \n62 4; AP, Astragalus polysaccharide; ApoE, Apolipoprotein E; ARE, Antioxidant response \n63 element; ASIV, Astragaloside IV; ATP, Adenosine triphosphate; ATM, Ataxia \n64 telangiectasia mutated; bFGF, Basic fibroblast growth factor; BTE, Black tea extract; CBF, \n65 Coronary blood flow; CCM, Compound Chinese medicine; CFs, Cardiac fibroblasts; CFR, \n66 Coronary flow reserve; CHM, Chinese herbal medicines; CL, Carthamus tinctorius L. and \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 4 / 58\n67 Lepidium apetalum Willd; CMD, Coronary microvascular dysfunction; CMVD, Coronary \n68 microvascular disease; CMECs, Cardiac microvascular endothelial cells; COX-2, \n69 Cyclooxygenase-2; CTSS, Cathepsin S; CVB3, Coxsackievirus B3; CYP, Alpha-Cyperone; \n70 CYT, Caffeoylxanthiazonoside; DG, GeGen DanShen extract; DGBX, DangGuiBuXue \n71 Tang; Diosmetin-7-O-glucoside, Diosmetin-7-O-β-D-glucopyranoside; DLF, DanLou \n72 formula; Drp1, Dynamin-related protein 1; ECE-1, Endothelin-converting enzyme-1; \n73 EGb761, Ginkgo biloba extract; EndMT, Endothelial-to-mesenchymal transition; eNOS, \n74 Endothelial nitric oxide synthase; ER, Estrogen receptor; ERK, Extracellular signal-\n75 regulated kinase; ERS, Endoplasmic reticulum stress; FGF, Fibroblast growth factor; FoxO, \n76 Forkhead-Box Class O; GAS, Gastrodin; GTP, Guanosine triphosphate; H3K9ac, Histone \n77 H3 lysine 9 acetylation; H/R, Hypoxia/Reoxygenation; Hcy, Homocysteine; HF, Heart \n78 failure; HFD, High fat diet; HG, High glucose; HIF, Hypoxia-inducible factor; HO-1, Heme \n79 oxygenase-1; HSP27, Heat shock protein 27; I/R, Ischemia/reperfusion; IκB, Inhibitor of \n80 NF-κB; IGF1R, Insulin-like growth factor 1 receptor; IHD, Ischemic heart disease; IL, \n81 Interleukin; iNOS, Inducible nitric oxide synthase; IRS1, Insulin receptor substrate 1; JAK, \n82 Janus tyrosine kinase; JAM, Junctional adhesion molecule; KLF, Krüppel-like factor; L-\n83 NAME, N(ω)-nitro-L-arginine-methyl ester; LDL-C, Low-density lipoprotein cholesterol; \n84 Linc-ROR, Long intergenic non-coding RNA regulator of reprogramming; LPS, \n85 Lipopolysaccharide; MAPK, Mitogen-activated protein kinase; MBC, Major bioactive \n86 component; MDA, Malondialdehyde; MDG-1, A water-soluble beta-D-fructan from O. \n87 japonicus; MEK, Mitogen-activated protein kinase; MF, Myocardial fibrosis; Mff, \n88 mitochondrial fission factor; MHBFC, 17-Methoxyl-7-hydroxy-benzene-furanchalcone; MI, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 5 / 58\n89 Myocardial infarction; MLC, Myosin light chain; MMP-9, Matrix metallopeptidase-9; mTOR, \n90 Mammalian target of rapamycin; NADPH, Nicotinamide adenine dinucleotide phosphate; \n91 NF-κB, Nuclear factor-kappa B; NLRP3, Nucleotide-binding oligomerization domain-like \n92 receptor protein 3; NO, Nitric oxide; NOS, Nitric oxide synthase; NR4A1, Nuclear receptor \n93 subfamily 4 group A member 1; Nrf2, Nuclear factor‑erythroid 2 related factor 2; NRG-1, \n94 Neuregulin-1; NT, Nitrotyrosine; OA, Oroxylin A; OJ, Ophiopogon japonicus; P-IκBα, \n95 Phosphorylated inhibitor of kappa B alpha; P-p65, Phosphorylated p65; P70S6k1, 70 kDa \n96 ribosomal protein S6 kinase 1; PAI, Plasminogen activator inhibitor; PDGF, Platelet-\n97 derived growth factor; PECAM-1, Platelet-endothelial cell adhesion molecule-1; PER, \n98 Periplocin; PGE2, Prostaglandin E2; PGIS, Prostacyclin synthase; PHDs, Prolyl \n99 hydroxylase domain enzymes; PI3K, Phosphatidylinositol 3-kinase; PINK, Phosphatase \n100 and tensin homolog-induced putative kinase; PLCδ3, Phospholipase Cδ3; PMN, \n101 Polymorphonuclear leukocyte; PN, Panax Notoginseng; PPAR-α, Peroxisome proliferator-\n102 activated receptor α; PRISMA, Preferred Reporting Items for Systematic Reviews and \n103 Meta-Analyses; Pyk, Proline-rich tyrosine kinase; Q, Quercetin; QLQX, QiLiQiangXin; \n104 QSYQ, QiShenYiQi; Rb3, Ginsenoside-Rb3; RG, Radix Ginseng; Rg3, Ginsenoside-Rg3; \n105 RhoA, Ras homolog gene family member A; RIP3, Receptor interacting protein 3; RLC, \n106 Rhizoma Ligustici Chuanxiong ; ROCK, Rho-associated protein kinase; ROS, Reactive \n107 oxygen species; RPS6KB1, Ribosomal protein S6 kinase B1; RS, Radix Scutellariae; RSV, \n108 Resveratrol; S1P, Sphingosine 1 phosphate; SA, Salidroside; SCU, Scutellarin; SL, \n109 ShenLian extract; SMF, ShenMai formula; SOD, Superoxide dismutase; SSNX, \n110 ShuangShenNingXin formula; STAT, Signal transducer and activator of transcription; \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 6 / 58\n111 STDP, SheXiangTongXin Dropping Pill; SXBX, SheXiangBaoXin Pill; Tan Ⅱ A, \n112 Tanshinone Ⅱ A; TCM, Traditional Chinese medicine; TF, Tissue factor ; TGF, \n113 Transforming growth factor; TJs, Tight junctions; TMYX, TongMaiYangXin pill; TNF-α, \n114 Tumor necrosis factor-α; TXD, TianXiangDan; TXL, TongXinLuo; VA, Velvet Antler; VAP, \n115 Velvet antler proteins; VE, Vascular endothelial; VEGF, Vascular endothelial growth factor; \n116 VMC, Viral myocarditis; VSMCs, Vascular smooth muscle cells; XQT, XiangQiTang; ZO-\n117 1, Zona occludens-1.\n118\n119 1. Introduction\n120 Coronary microvascular disease (CMVD) is a clinical condition characterized by \n121 objective evidence of exertional angina and/or myocardial ischemia resulting from \n122 structural and/or functional abnormalities in the coronary microcirculation, triggered by \n123 various etiological factors. Coronary microvascular dysfunction (CMD) represents a crucial \n124 mechanism underlying CMVD [1]. CMD is implicated in different stages of cardiovascular \n125 disease and serves as a significant adverse prognostic factor for patients with ischemic \n126 heart disease (IHD) [2]. In recent years, CMD has garnered increasing attention due to its \n127 clinical relevance. Notwithstanding the high prevalence of CMD, effective treatment \n128 remains elusive. Therapeutic interventions such as nicorandil, statins, and angiotensin-\n129 converting enzyme inhibitors may offer potential benefits [3, 4]. However, the complete \n130 clinical picture remains incompletely understood. Traditional Chinese medicine (TCM), \n131 which has been utilized in clinical practice throughout China for nearly two millennia, has \n132 shown promise as a clinically viable approach for treating CMD [5, 6]. \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 7 / 58\n133 The development of CMD is significantly influenced by structural and/or functional \n134 abnormalities in cardiac microvascular endothelial cells (CMECs) [7]. In a physiological \n135 setting, the coronary microcirculation serves as the primary resistance artery in the \n136 coronary arteries. And it plays a crucial role in regulating coronary blood flow (CBF) [8]. \n137 CMECs, which constitute approximately one-third of all heart cells [9], are essential \n138 components of the coronary microcirculation [7], They play a critical role in controlling CBF \n139 and maintaining proper coronary microvascular function [10, 11]. When stimulated by \n140 pathological factors, CMECs lose their ability to proliferate, adhere, migrate normally or \n141 undergo apoptosis and secrete substances as usual. This can lead to abnormal contraction \n142 and diastolic function in microvessels as well as compromised integrity of the \n143 microvascular barrier and thinning of coronary microarterioles [12, 13]. Ultimately, this may \n144 result in reduced coronary flow reserve (CFR) and inadequate myocardial blood supply \n145 [14]. Therefore, investigating the mechanism through which compound Chinese medicine \n146 (CCM) and its constituents intervene in CMECs under various injury models can provide \n147 valuable insights into the potential of TCM for treating CMD. This review aims to present \n148 the latest evidence on TCM intervention mechanisms in CMECs under diverse injury \n149 models.\n150 2. Methods\n151 The systematic literature review was conducted in accordance with the guidelines \n152 outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses \n153 (PRISMA) statement [15] (S1 Table). The systematic review has been registered in the \n154 INPLASY platform for prospective registration with the registration number \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 8 / 58\n155 INPLASY202470092. Protocol details are available at INPLASY Protocol 6561 – INPLASY. \n156 Ethical approval was not required due to no human subjects being involved in this study.\n157 2.1. Search Strategy\n158 From database construction until March 2024, the electronic databases utilized for \n159 literature search encompassed PubMed, Embase, Web of Science, Scopus, China \n160 National Knowledge Infrastructure and China Biology Medicine disc. The keywords \n161 employed were “Chinese herbal medicine monomer”, “Chinese herbal medicine \n162 components”, “Chinese herbal compound”, “traditional Chinese medicine”, “herbal \n163 medicine”, “Chinese herbal medicine”, “Chinese herb”, “CHM”, “TCM”, “China Chinese \n164 herbal medicine”, “China extract”, “China fraction”, “China formula”, “China prescription, \n165 \"CMECs\", \"CMEC\", \"coronary microvascular endothelial cells\", \"cardiac microvascular \n166 endothelial cells\", \"myocardiac microvascular endothelial cells\". The search scope was \n167 limited to full-text articles without any additional restrictions.\n168 2.2. Flowchart Sketch of the Screening Process\n169 The flowchart illustrating the systematic review screening process is presented in Fig \n170 1. Initially, a total of 296 literature sources were identified and evaluated. Following a de-\n171 weighting procedure, 84 papers were excluded, while 212 papers met the inclusion criteria. \n172 The inclusion criteria consisted of the following: 1) the literature had to be written in English; \n173 2) it had to be the full text; 3) the content of the literature had to be related to Chinese \n174 herbal medicines (CHM); 4) the study design had to involve CMECs or cardiac \n175 microvasculature. On the other hand, the exclusion criteria encompassed irrelevant \n176 literature, reviews, meta-analyses, case reports, conference proceedings, book chapters, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 9 / 58\n177 letters to the editor, oral presentations, posters, and editorials. During the initial screening, \n178 128 papers were excluded based on a skim of the title or abstract, leaving 84 papers for \n179 further evaluation. Among these, 12 papers lacked full text in English, 7 papers did not \n180 involve CMECs or cardiac microvessels in their design, and 2 papers were not focused on \n181 heart-related research. These 21 papers were consequently excluded. Finally, a total of 63 \n182 relevant studies were included in this review. Among them, 19 studies employed models \n183 of ischemic or hypoxic injury, 16 studies utilized models of ischemia/reperfusion (I/R) or \n184 hypoxia/reoxygenation (H/R) injury, 10 studies employed models of inflammatory injury, \n185 and 18 studies employed models of other types of injury, based on cellular processing \n186 methods (S2 Table). This review aims to comprehensively report and critically analyze the \n187 relevant studies. However, it should be noted that a meta-analysis was not conducted.\n188 Fig 1. PRISMA flow chart.\n189 3. Results\n190 Among the 64 papers included, the intervention methods employed for CMECs \n191 exhibited considerable variation. Based on the specific cellular treatments applied, the \n192 literature can be categorized into distinct injury models, including ischemic or hypoxic injury, \n193 I/R or H/R injury, inflammatory injury, metabolic injury, angiotensin II (Ang II) injury, as well \n194 as other treatments. In these studies, a total of 16 CCMs and 18 major bioactive \n195 components (MBCs) were included. The CCMs and MBCs that are effective in regulating \n196 CMECs under various injury models are listed in S3 and S4 Tables. In the subsequent \n197 paragraphs, we will delve into a comprehensive review of the roles played by CCM and its \n198 constituents in different injury models, along with the underlying pathway mechanisms \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 10 / 58\n199 implicated. \n200 3.1. TCM that Modify CMECs in Ischemic or Hypoxic \n201 Injury Model\n202 Ischemia- and hypoxia-induced injury is widely regarded as the underlying \n203 pathological basis and initial process of numerous cardiovascular conditions. Protecting \n204 CMECs from injury caused by ischemia and hypoxia represents a crucial therapeutic \n205 approach for addressing a range of cardiovascular diseases [16]. Studies have discovered \n206 that TCM compounds or core constituents in regulating this injury plays a certain influence. \n207 and the involved mechanisms are illustrated in Fig 2 and summarized in Table 1. \n208 Fig 2. TCM regulate various signaling pathways that mediate CMECs dysfunction \n209 induced by hypoxia or ischemia. Akt, Protein kinase B; ALDH, Aldehyde dehydrogenase; \n210 ATP, Adenosine triphosphate; bFGF, Basic fibroblast growth factor; CCM, Compound \n211 Chinese medicine; CL, Carthamus tinctorius L. and Lepidium apetalum Willd; DGBX, \n212 DangGuiBuXue Tang; EGb761, Ginkgo biloba extract; eNOS, Endothelial nitric oxide \n213 synthase; ERK, Extracellular signal-regulated kinase; DG, GeGen DanShen extract; HIF, \n214 Hypoxia-inducible factor; IRF5, Interferon regulatory factor 5; KLF, Krüppel-like factor; \n215 MDG-1, A water-soluble beta-D-fructan from O. japonicus; MI, Myocardial infarction; \n216 mTOR, Mammalian target of rapamycin; NRG-1, Neuregulin-1; OGD, Oxygen glucose \n217 deprivation; PI3K, Phosphoinositide 3-kinase; QLQX, QiLiQiangXin; QSYQ, QiShenYiQi; \n218 S1P, Sphingosine 1 phosphate; STDP, Shexiang Tongxin Dropping Pill; SXBX, \n219 SheXiangBaoXin Pill; Syk, Spleen tyrosine kinase; TGF, Transforming growth factor; TJs, \n220 Tight junctions; TXL, TongXinLuo; VA, Velvet Antler; VAP, Velvet Antler Proteins; VEGF, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 11 / 58\n221 Vascular endothelial growth factor; VEGFR, Vascular endothelial growth factor receptor.\n222 Table 1. Effects of CCM, CMM and MBC injury induced by hypoxia or ischemic.\nCCM, \nCMM and \nMBC\nIn \nvitro/In \nvivo\nModel (cells) Model (animals) Signaling pathways Effects References\nCL Both Rat CMECs \n(Hypoxia 48 hours)\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MI）\nTGFβ1/Snail \nsignaling pathway 8;9; Zhou et al. \n(2023)\nQLQX In vitro Rat CMECs \n(Hypoxia 24 hours) /\nmiR-21/HIF-\n1α/VEGF signaling \npathway\n10; Wang et al. \n(2021)\nIn vitro Rat CMECs \n(Hypoxia 12 hours) /\nHIF-1α/VEGF \nsignaling pathway; \nAMPK/mTOR/HIF-1α \nsignaling pathway\n1;2;3;\n10;\nWang et al. \n(2018)\nIn vitro Rat CMECs \n(Hypoxia 12 hours) /\nNRG-1/ErbB \nsignaling pathway; \nPI3K/AKT/mTOR \nsignaling pathway; \nHIF-1α/VEGF \nsignaling pathway\n3;10;\nWang J. F. \net al. \n(2017)\nQSYQ In vitro\nRat CMECs was \nfrom myocardial \ninfarction in rat \nwhich using the \nligature method\n/\nmir-223-\n3p/RPS6KB1/HIF-1α \nsignaling pathway\n10; Dai et al. \n(2016)\nSTDP In vivo /\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MI）\nDectin-1/Syk/IRF5 \nsignaling pathway 4;6;11; Cui et al. \n(2023)\nDGBX In vivo /\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MI）\nVEGF/VEGFRs \nsignaling pathway 10; Hu et al. \n(2018)\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 12 / 58\nTXL Both Human CMECs \n(Hypoxia 3 days)\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MF)\nNRG-1/ErbB \nsignaling pathway; \nPI3K/AKT signaling \npathway\n8; Yin et al. \n(2019)\nIn vitro\nHuman CMECs \n(stimulated with \nCoCl2 for 24 hours)\n/ H3K9ac/claudin-9 6; Liu et al. \n(2016)\n/ KLF4, TJ proteins 6; Zheng et al. \n(2015)In vitro\nHuman CMECs \n(stimulated with \nCoCl2 for 24 hours)\nIn vitro\nHuman CMECs \n(stimulated with \nCoCl2)\n/ HIF-2α/VEGF \nsignaling pathway 2;4; Li Y. N. et \nal. (2015)\nDG In vivo /\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MI)\nVEGF/VEGFR2 \nsignaling pathway 10; Zhai et al. \n(2021)\nEGb 761 In vivo /\n16.5-17 months \nmale wistar rats \n(Hypoxia 20min)\n/ 15; Welt et al. \n(1996)\nVA In vivo /\nSD male rats (Left \nanterior \ndescending \ncoronary ligation-\ninduced MI）\nNotch signaling \npathway; VEGF \nsignaling pathway\n10; Li et al. \n(2018)\nVAP In vitro\nRat CMECs \n(Hypoxic-Ischemic \n46 hours)\n/ PI3K/AKT signaling \npathway 3;10; Xiao et al. \n(2017)\nSXBX In vitro Rat CMECs \n(Hypoxia 24 hours) / ALDH2/AKT/mTOR \nsignaling pathway 3;10; Hu et al. \n(2021)\nMDG-1 In vitro Human CMECs \n(OGD 8 hours) /\nS1P/bFGF/AKT/ERK\n/eNOS signaling \npathway\n10;\nWang S. O. \net al. \n(2010)\nBoth Human CMECs \n(OGD 8 hours)\nSD male rats \n(Paraconal \ninterventricular \nbranch of the left \ncoronary \nligation）\nS1P/AKT/ERK \nsignaling pathway 9; Wang et al. \n(2012)\n223 Akt, Protein kinase B; ALDH, Aldehyde dehydrogenase; bFGF, Basic fibroblast \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 13 / 58\n224 growth factor; CCM, Compound Chinese medicine; CL, Carthamus tinctorius L. and \n225 Lepidium apetalum Willd; CMECs, Cardiac microvascular endothelial cells; CMM, \n226 Chinese materia medica; DGBX, DangGuiBuXue Tang; EGb 761, Ginkgo biloba \n227 extract; eNOS, Endothelial nitric oxide synthase; ERK, Extracellular signal-regulated \n228 kinase; DG, GeGen DanShen extract; HIF, Hypoxia-inducible factor; IRF5, Interferon \n229 regulatory factor 5; KLF, Krüppel-like factor; MBC, Major bioactive component; MDG-\n230 1, A water-soluble beta-D-fructan from O. japonicus; MI, Myocardial infarction; \n231 mTOR, Mammalian target of rapamycin; NRG-1, Neuregulin-1; OGD, Oxygen \n232 glucose deprivation; PI3K, Phosphoinositide 3-kinase; QLQX, QiLiQiangXin; QSYQ, \n233 QiShenYiQi; S1P, Sphingosine 1 phosphate; SD, Sprague-Dawley; STDP, \n234 SheXiangTongXin Dropping Pill; SXBX, SheXiangBaoXin Pill; Syk, Spleen tyrosine \n235 kinase; TGF, Transforming growth factor; TJs, Tight junctions; TXL, TongXinLuo; VA, \n236 Velvet Antler; VAP, Velvet Antler Proteins; VEGF, Vascular endothelial growth factor; \n237 VEGFR, Vascular endothelial growth factor receptor; 1, Regulation of energy \n238 metabolism; 2, Attenuation of oxidative stress; 3, Anti-apoptosis; 4, Inhibition of \n239 inflammatory cytokines release; 5, Regulation of adhesion molecule expression; 6, \n240 Alleviation microvascular hyperpermeability; 7, Repression autophagy; 8, Inhibition of \n241 fibrosis; 9, Controlling both paracrine and autocrine processes; 10, Promotion of \n242 microvascular generation; 11, Dilation of coronary microvessels; 12, Cell senescence \n243 mitigation; 13, Reducing potential microthrombosis; 14, Anti-pyroptosis; 15, \n244 Improving the structure of the cell.\n245\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 14 / 58\n246 Ischemia or hypoxia can potentially impede angiogenesis. Animal studies have shown \n247 that Velvet Antler (VA), GeGen DanShen extract (DG), and DangGuiBuXue Tang (DGBX) \n248 can effectively mitigate the damage caused by myocardial infarction (MI) and enhance \n249 microvessel density within the infarct zone [17-19]. SheXiangTongXin Dropping Pill (STDP) \n250 demonstrated the ability to prevent microvascular leakage, reduce edema, hemorrhage, \n251 and inflammatory cell infiltration in the tissues surrounding the microvessels, while \n252 preserving the morphological integrity of myocardial microvessels [20]. Another study \n253 discovered that Ginkgo biloba extract (EGb761) can protect the ultrastructure of CMECs \n254 against hypoxia [21].\n255 Hypoxia-inducible factor (HIF) is recognized as the major transcriptional regulator of \n256 the adaptive response to hypoxia [22]. The presence of HIF-1α stimulates the expression \n257 of various angiogenic factors, including transforming growth factor (TGF)-α, platelet-\n258 derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) [23]. \n259 QiLiQiangXin (QLQX) has been shown to protect CMECs from hypoxia-induced injury by \n260 promoting angiogenesis and CMECs proliferation through the activation of the miR-21/HIF-\n261 1α/VEGF axis and HIF-1α-mediated glycolysis promotion [24]. In an alternative study, \n262 QLQX was found to induce the adenosine 5'-monophosphate-activated protein kinase \n263 (AMPK)/mammalian target of rapamycin (mTOR)/HIF-1α signaling pathway, leading to \n264 increased HIF-1α protein expression in hypoxic CMECs. The stability of HIF-1α and its \n265 activation of genes are closely associated with prolyl hydroxylase domain enzymes (PHDs) \n266 [25], and QLQX was found to downregulate the expression of PHDs, thereby enhancing \n267 HIF-1α stability [26]. Neuregulin-1 (NRG-1), a cardioactive growth factor released from \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 15 / 58\n268 endothelial cells, is indispensable for cardiac development, structural maintenance, and \n269 functional integrity of the heart. They transmit their signals through interactions with cell \n270 membrane receptors of the ErbB family [27]. QLQX activates the phosphatidylinositol 3-\n271 kinase (PI3K)/protein kinase B (AKT)/mTOR signaling pathway, which further activates the \n272 HIF-1α/VEGF signaling pathway to protect against hypoxia. This mechanism is mediated \n273 by the NRG-1/ErbB signaling pathway [28].\n274 TongXinLuo (TXL) has been previously investigated as a potential treatment for luo \n275 illness. Both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are \n276 inducible enzymes involved in oxidative stress and inflammation [29, 30]. In hypoxia-\n277 induced human CMECs, TXL was found to inhibit the production of VEGF, HIF-2α, COX-\n278 2, and iNOS. High doses of TXL were found to inhibit hypoxia-induced increases in the \n279 levels of the inflammatory mediator prostaglandin E2 (PGE2) and the oxidative marker \n280 nitrotyrosine (NT), thereby attenuating inflammation and oxidative damage. However, TXL \n281 did not enhance the expression of prostacyclin synthase (PGIS) or endothelial nitric oxide \n282 synthase (eNOS) [31]. PGIS possesses anti-inflammatory properties and cytoprotective \n283 effects [32], while eNOS expression promotes blood vessel dilation [33]. Macrophages \n284 have been implicated in hypoxia-induced injury to human CMECs, and peroxynitrite is \n285 involved in this process. Another study found that TXL can increase the expression of PGIS \n286 primarily and reduce endothelin-converting enzyme-1 (ECE-1) expression through \n287 inhibiting macrophage-mediated nitrotyrosine accumulation [34]. Notably, ECE-1 plays a \n288 crucial role in the signaling pathway for endothelin and serves as a significant modulator \n289 of vascular tone [35].\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 16 / 58\n290 The integrity of the microvascular barrier relies on various factors, including the \n291 subendothelial basement membrane, caveolin quantity and function in endothelial cells, \n292 and the presence of adherens junctions (AJs) and tight junctions (TJs) between adjacent \n293 CMECs [36]. TJs proteins encompass occludin, claudin, and junctional adhesion molecule \n294 (JAM), which are transmembrane proteins [37] AJs are responsible for calcium-mediated \n295 homophilic adhesion between neighboring cells through cadherin, including zona \n296 occludens 1 (ZO-1) protein, β-catenin, vascular endothelial (VE)-cadherin, among others \n297 [38, 39]. TXL can reverse the hypoxia-inhibited claudin-9 expression by elevating histone \n298 H3 lysine 9 acetylation (H3K9ac) in the promoter region of its gene [40]. Furthermore, TXL \n299 provides protection by enhancing the phosphorylation of krüppel-like factor (KLF) 4, a basic \n300 transcription factor that regulates the production of occludin, claudin-1, VE- cadherin, and \n301 β-catenin [41]. \n302 The transcriptional repressor snail can induce the endothelial-to-mesenchymal \n303 transition (EndMT). The resultant EndMT-derived cardiac fibroblasts (CFs), synthesize \n304 large amounts of collagen, which contributes to fibrotic lesions and abnormal collagen fiber \n305 deposition [42]. TXL inhibits EndMT by downregulating snail expression in CMECs after \n306 three days of hypoxia and activates the NRG-1/ErbB/PI3K/AKT signaling pathway to \n307 reduce myocardial fibrosis (MF) following acute MI [43]. Hypoxia for 48 hours activates the \n308 TGF-β1/snail signaling pathway, and the Carthamus tinctorius L. and Lepidium apetalum \n309 Willd drug pair (CL) can inhibit EndMT in CMECs by inhibiting the TGF-β1/snail signal \n310 pathway [44]. \n311 QiShenYiQi (QSYQ) downregulate the expression of mir-223-3p, activate the \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 17 / 58\n312 ribosomal protein S6 kinase B1 (RPS6KB1)/HIF-1α signaling pathway, and facilitate \n313 ischemic cardiac angiogenesis [45]. A study on Ophiopogon japonicus and its water-\n314 soluble beta-D-fructan (MDG-1) revealed that the sphingosine 1 phosphate \n315 (S1P)/AKT/extracellular signal-regulated kinase (ERK) signaling pathway might be \n316 involved in the potential mechanism of their anti-ischemic action on cell survival [46]. Basic \n317 fibroblast growth factor (bFGF) is a prominent factor that stimulates endothelial cell \n318 proliferation and neovascularization by binding to the fibroblast growth factor (FGF) \n319 receptor [47]. Another investigation demonstrated that MDG-1 could promote angiogenesis \n320 by protecting human CMECs and cardiomyocytes from ischemia-induced cellular damage \n321 through the S1P/bFGF/AKT/ERK/eNOS signaling pathway [48]. SheXiangBaoXin Pill \n322 (SXBX) promotes angiogenesis through the aldehyde dehydrogenase \n323 (ALDH)2/AKT/mTOR signaling pathway [49]. Velvet antler proteins (VAP) safeguards \n324 CMECs against ischemia-hypoxia by modulating the PI3K/AKT signaling pathway [50].\n325 3.2. TCM that Modify CMECs in I/R or H/R Injury Model\n326 I/R-induced damage to the microcirculation can lead to increased leukocyte adhesion, \n327 reactive oxygen species (ROS) production, dysfunction of CMECs, and leakage of \n328 macromolecules. These events can trigger inflammatory responses, impair CBF, and \n329 ultimately result in cardiomyocyte death. Therefore, the preservation of CMECs and the \n330 reduction of CMD following I/R are considered promising approaches in the treatment of \n331 cardiac I/R injury [51]. \n332 Studies have demonstrated that TCM can inhibit apoptosis, regulate the expression \n333 of adhesion molecules, alleviate microvascular permeability, dilate coronary microvessels, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 18 / 58\n334 mitigate microvascular obstruction, modulate oxidative stress, and control inflammation, \n335 among other effects. According to research on animals, the DanLou formula (DLF) and the \n336 TongMaiYangXin pill (TMYX) enhance myocardial no-reflow following I/R [52, 53]. \n337 Resveratrol (RSV) and scutellarin (SCU) have been found to regulate the production of \n338 intracellular proteins and the paracrine secretion function of CMECs following H/R damage \n339 [54, 55]. The specific effects and underlying mechanisms of action are illustrated in Fig 3 \n340 and summarized in Table 2.\n341 Fig 3. TCM regulate various signaling pathways that mediate CMECs dysfunction \n342 induced by I/R or H/R. AKT, Protein kinase B; AP, Astragalus polysaccharide; ASIV, \n343 Astragaloside IV; ATM, Ataxia telangiectasia mutated; ATP, Adenosine triphosphate; Drp1, \n344 Dynamin-related protein 1; EGb761, Ginkgo biloba extract; eNOS, Endothelial nitric oxide \n345 synthase; ERK, Extracellular signal-regulated kinase; GAS, Gastrodin; H/R, \n346 Hypoxia/Reoxygenation; I/R, Ischemia/reperfusion; IGF1R, Insulin-like growth factor 1 \n347 receptor; iNOS, Inducible nitric oxide synthase; IRS1, Insulin receptor substrate 1; MAPK, \n348 Mitogen-activated protein kinase; MEK, Mitogen-activated protein kinase; Mff, \n349 Mitochondrial fission factor; NLRP3, Nucleotide-binding oligomerization domain-like \n350 receptor protein 3; NR4A1, Nuclear receptor subfamily 4 group A member 1; PI3K, \n351 Phosphoinositide 3-kinase; PINK, Phosphatase and tensin homolog-induced putative \n352 kinase; QSYQ, QiShenYiQi; SCU, Scutellarin; SL, ShenLian extract; SSNX, \n353 ShuangShenNingXin formula; TXL, TongXinLuo.\n354 Table 2. Effects of CCM, CMM and MBC injury induced by I/R or H/R.\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 19 / 58\nCCM, \nCMM and \nMBC\nIn \nvitro/in \nvivo\nModel (cells) Model (animals) Signaling pathways Effects Reference\ns\nSL Both\nRat CMECs （OGD 2 \nhours and \nreoxygenation and \nresupply of glucose 2 \nhours）\nWistar male rats\n（Ischemia 2 \nhours and \nreperfusion 24 \nhours）\nPINK/Parkin \nsignaling pathway 4;6;7;13; Li et al. \n(2023)\nASIV Both\nHuman CMECs \n（Hypoxia 2 hours \nand reoxygenation 2 \nhours）\nSD male rats\n（Ischemia 30min \nand reperfusion \n90 min）\nIGF1R/IRS1/PI3K/A\nKT signaling \npathway\n1;6; He et al. \n(2022)\nAP In vitro\nHuman CMECs \n（OGD 2 hours and \nreoxygenation and \nresupply of glucose 24 \nhours）\n/ p38 MAPK \nsignaling pathway 5; Zhu et al. \n(2013)\nRSV In vitro\nHuman CMECs \n（Hypoxia 12 hours \nand reoxygenation 2 \nhours）\n/ / 3;4;9; Cui et al. \n(2022)\nQSYQ Both\nHuman CMECs \n（Hypoxia 2 hours \nand reoxygenation 3 \nhours）\nSD male rats\n（Ischemia 30min \nand reperfusion \n90 min）\nSrc/caveolin-1 \nsignaling pathway; \nRhoA/ROCK/MLC \nsignaling pathway\n1;6;9; Pan et al. \n(2021)\nSSNX Both\nCMECs （OGD 4 \nhours and \nreoxygenation and \nresupply of glucose 2 \nhours）\nSD male rats\n（Ischemia 45 \nmin and \nreperfusion 24 \nhours）\nNR4A1/mff/Drp1 \nsignaling pathway\n1;3;10;1\n1;\nLiu et al. \n(2024)\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 20 / 58\nGAS Both\nHuman CMECs \n（Hypoxia 2 hours \nand reoxygenation 2 \nhours）\nI/R NLRP3/caspase-1 \nsignaling pathway 4;14; Sun et al. \n(2019)\nEGb 761 In vitro\nRat CMECs \n（Hypoxia 2 hours \nand reoxygenation）\n/ ATM signaling \npathway 2;3; Zhang et \nal. (2017)\nTXL Both\nHuman CMECs \n（Hypoxia 18 hours \nand reoxygenation 2 \nhours）\nSD male rats\n（Ischemia 45 \nmin and \nreperfusion 3 \nhours）\nmiR-145-\n5p/p70s6k1/eNOS \nsignaling pathway\n11;\nChen GH. \net al. \n(2020)\nIn vitro\nHuman CMECs \n（Hypoxia 2 hours \nand reoxygenation 2 \nhours）\n/ / 3; Li Q. et al. \n(2017)\nIn vitro\nHuman CMECs \n（Hypoxia 12 hours \nand reoxygenation 2 \nhours）\n/ / 3;9; Cui et al. \n(2016)\nIn vitro\nHuman CMECs \n（Hypoxia 2 hours \nand reoxygenation 2 \nhours）\n/ MEK/ERK signaling \npathway 3;7; Cui et al. \n(2014)\nSCU In vitro\nHuman CMECs \n（Hypoxia 12 hours \nand reoxygenation 12 \nhours）\n/ / 9; Shi et al. \n(2015)\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 21 / 58\nDLF in vivo /\nSD male rats\n（Ischemia 60 \nmin and \nreperfusion 2 \nhours）\neNOS/iNOS \nsignaling pathway 11;13; Dai et al. \n(2021)\nTMYX in vivo /\nSD male rats\n（Ischemia 2 \nhours and \nreperfusion）\nPI3K/AKT/eNOS \nsignaling pathway 11; Chen R. et \nal. (2020)\nextracts \nfrom 12 \nChinese \nedible \nflowers\nIn vitro\nRat CMECs \n（Hypoxia 1 hours \nand reoxygenation 1 \nhours）\n/ / 2;3; Wang F. et \nal. (2017)\n355 AKT, Protein kinase B; AP, Astragalus polysaccharide; ASIV, Astragaloside IV; ATM, \n356 Ataxia telangiectasia mutated; CCM, Compound Chinese medicine; CMECs, Cardiac \n357 microvascular endothelial cells; CMM, Chinese materia medica; DLF, DanLou formula; \n358 Drp1, Dynamin-related protein 1; EGb761, Ginkgo biloba extract; eNOS, Endothelial nitric \n359 oxide synthase; ERK, Extracellular signal-regulated kinase; GAS, Gastrodin; H/R, \n360 Hypoxia/Reoxygenation; I/R, Ischemia/reperfusion; IGF1R, Insulin-like growth factor 1 \n361 receptor; iNOS, Inducible nitric oxide synthase; IRS1, Insulin receptor substrate 1; MAPK, \n362 Mitogen-activated protein kinase; MBC, Major bioactive component; MEK, Mitogen-\n363 activated protein kinase; Mff, Mitochondrial fission factor; NLRP3, Nucleotide-binding \n364 oligomerization domain-like receptor protein 3; NR4A1, Nuclear receptor subfamily 4 group \n365 A member 1; OGD, Oxygen glucose deprivation; PI3K, Phosphoinositide 3-kinase; PINK, \n366 Phosphatase and tensin homolog-induced putative kinase; QSYQ, QiShenYiQi; RSV, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 22 / 58\n367 Resveratrol; SCU, Scutellarin; SL, ShenLian extract; SSNX, ShuangShenNingXin formula; \n368 TMYX, TongMaiYangXin pill; TXL, TongXinLuo; 1, Regulation of energy metabolism; 2, \n369 Attenuation of oxidative stress; 3, Anti-apoptosis; 4, Inhibition of inflammatory cytokines \n370 release; 5, Regulation of adhesion molecule expression; 6, Alleviation microvascular \n371 hyperpermeability; 7, Repression autophagy; 8, Inhibition of fibrosis; 9, Controlling both \n372 paracrine and autocrine processes; 10, Promotion of microvascular generation; 11, Dilation \n373 of coronary microvessels; 12, Cell senescence mitigation; 13, Reducing potential \n374 microthrombosis; 14, Anti-pyroptosis; 15, Improving the structure of the cell.\n375\n376 Through the ras homolog gene family member A (RhoA)/Rho-associated protein \n377 kinase (ROCK)/myosin light chain (MLC) signaling pathway, QSYQ have been found to \n378 inhibit I/R-induced cardiac microvascular hyperpermeability. Src family protein tyrosine \n379 kinases are known to be associated with endothelial cell permeability [56]. QSYQ has been \n380 shown to attenuate the upregulation of Src, p-caveolin-1, matrix metallopeptidase-9 (MMP-\n381 9), and cathepsin S (CTSS) induced by H/R, while also preserving the expression of \n382 claudin-5. Among the signaling pathways involved in mediating the effects of QSYQ, the \n383 Src/caveolin-1 pathway has been implicated [57]. \n384 Astragaloside IV (ASIV), the main active ingredient in QSYQ, has been found to \n385 protect the microvascular endothelial barrier. ASIV mitigates adenosine triphosphate (ATP) \n386 depletion, enhances the expression of tight junction proteins between endothelial cells, \n387 and promotes the H/R-induced activation of the insulin-like growth factor 1 receptor (IGF1R) \n388 and downstream phosphorylation of insulin receptor substrate 1 (IRS1)/PI3K/AKT \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 23 / 58\n389 signaling pathway [58]. \n390 Following I/R, the release of cytokines, oxygen radicals, and pro-inflammatory \n391 mediators stimulates the vascular endothelium and neutrophils. This leads to the \n392 upregulation of adhesion molecules, promoting the adhesion and migration of white blood \n393 cells across the vascular endothelium [59]. Astragalus polysaccharide (AP), a key \n394 component of QSYQ, reduces the expression of relevant adhesion molecules following I/R. \n395 AP also inhibits the interaction between human CMECs and polymorphonuclear leukocyte \n396 (PMN) during I/R by suppressing the p38 mitogen-activated protein kinase (MAPK) \n397 signaling pathway and downregulating the expression of adhesion molecules (P-selectin \n398 and E-selectin) in human CMECs [60].\n399 TXL has been shown to exert a protective effect against H/R injury, inhibit apoptosis \n400 in CMECs, and regulate protein expression and paracrine function in these cells [61, 62]. \n401 In cardiomyocytes treated with TXL following H/R, vesicles containing long intergenic non-\n402 coding RNA regulator of reprogramming (Linc-ROR) are released and taken up by CMECs. \n403 Subsequently, Linc-ROR downregulates its target miR-145-5p, which in turn promotes the \n404 production of 70 kDa ribosomal protein S6 kinase 1 (P70S6k1) and activates the eNOS \n405 pathway in CMECs [63]. Autophagy is an essential cellular process involved in the \n406 degradation of aging or dysfunctional organelles and protein aggregates, serving as a \n407 quality control mechanism. Impaired autophagy leads to the accumulation of dysfunctional \n408 organelles and proteins, resulting in endoplasmic reticulum stress (ERS) and apoptosis \n409 [64]. TXL has been found to induce autophagy via activation of the mitogen-activated \n410 protein kinase (MEK)/ERK signaling pathway, thereby protecting human CMECs from H/R \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 24 / 58\n411 injury [65].\n412 I/R injury in CMECs induces signaling pathways involved in both mitochondrial division \n413 and apoptosis. ShenLian extract (SL) has been shown to prevent mitochondrial autophagy \n414 and preserve mitochondrial activity, thereby reducing endothelial cell death, preserving \n415 endothelial cell function, and protecting the microvasculature, which ultimately helps \n416 mitigate coronary artery no-reflow. The phosphatase and tensin homolog-induced putative \n417 kinase (PINK)/Parkin signaling pathway is implicated in this process [66]. \n418 ShuangShenNingXin formula (SSNX) restores mitochondrial division to normal levels \n419 and inhibits mitochondrial apoptosis, thereby reducing potential damage to the \n420 mitochondrial membrane and preventing its opening. The mechanism underlying the \n421 effects of SSNX may involve the nuclear receptor subfamily 4 group A member 1 \n422 (NR4A1)/mitochondrial fission factor (Mff)/dynamin-related protein 1 (Drp1) signaling \n423 pathway [67]. NR4A1 has been shown to regulate mitochondrial fission [68]. Mff is known \n424 to stimulate mitochondrial fission by recruiting Drp1, a critical protein involved in the control \n425 of mitochondrial division. Pathological mitochondrial fission in CMECs can trigger \n426 unfavorable mitochondrial apoptotic pathways [69].\n427 Oxidative stress is a crucial factor in I/R injury, and ROS play a central role in \n428 mediating oxidative stress [70]. EGb761 has been shown to inhibit the I/R-induced \n429 activation of the ataxia telangiectasia mutated (ATM) pathway, thereby ameliorating \n430 apoptosis by suppressing ROS expression [71]. In a study evaluating the antioxidant \n431 effects of 12 edible flowers. Most of the edible flowers examined demonstrated the \n432 potential to enhance the antioxidant capacity of CMECs following I/R. Honeysuckle, rose, \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 25 / 58\n433 and wild chrysanthemum were found to exhibit the highest levels of antioxidant activity \n434 [72].\n435 The nucleotide-binding oligomerization domain-like receptor protein 3 \n436 (NLRP3)/caspase-1 signaling pathway is believed to play a critical role in the injury to \n437 CMECs and cardiac tissues, as well as the increase in infarct area during I/R injury. \n438 Gastrodin (GAS) has been shown to partially reverse the pyroptosis of CMECs and reduce \n439 the area of MI and inflammatory cell infiltration by inhibiting the NLRP3/caspase-1 signaling \n440 pathway [73]. \n441 3.3. TCM that Modify CMECs in Inflammatory Injury \n442 Model\n443 Vascular inflammation plays a significant role in the pathogenesis of CMD [74], It can \n444 lead to damage in coronary microvessels, as well as promote thrombosis and perivascular \n445 fibrosis. The vascular endothelium, acting as a barrier between the vascular lumen and \n446 surrounding tissue, serves as a key regulator and participant in the vascular inflammatory \n447 response [75]. Inflammatory substances such as tumor necrosis factor-α (TNF-α), \n448 homocysteine (Hcy), and lipopolysaccharide (LPS) are known to induce inflammation in \n449 cells [76-78]. TCM exerts its effects on enhancing CMECs following vascular inflammatory \n450 injury mainly through modulation of the nuclear factor-kappa B (NF-κB), MAPKs, and Janus \n451 tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) signaling \n452 pathways [79, 80]. For instance, ShenMai formula (SMF), 4-O-(2-O-acetyl-6-O-p-\n453 coumaroyl-β-D-glucopyranosyl)-p-coumaric acid (4-ACGC) isolated from Bidens pilosa \n454 Linn., and salidroside (SA) have been shown to impact the development of vascular \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 26 / 58\n455 inflammation [76, 81, 82]. Fig 4 and Table 3 provide a visual representation of the \n456 underlying mechanisms and the expression of relevant inflammatory mediators.\n457 Fig 4. TCM regulate various signaling pathways that mediate CMECs dysfunction \n458 induced by inflammation. 4-ACGC, 4-O-(2″-O-acetyl-6″-O- p-coumaroyl-β-D-\n459 glucopyranosyl) -p-coumaric acid; AND, Andrographolide; ASIV, Astragaloside IV; CYP, \n460 Alpha-Cyperone; CYT, Caffeoylxanthiazonoside; Hcy, Homocysteine; HO-1, Heme \n461 oxygenase-1; IL, Interleukin; JAK, Janus tyrosine kinase; KLF, Krüppel-like factor; LPS, \n462 lipopolysaccharide; MAPK, Mitogen-activated protein kinase; MDA, Malondialdehyde; NF-\n463 κB, Nuclear factor-kappa B; Nrf2, Nuclear factor-erythroid 2 related factor 2; QLQX, \n464 QiLiQiangXin; SA, Salidroside; SD, Sprague Dawley; SMF, ShenMai formula; SOD, \n465 Superoxide Dismutase; STAT, Signal transduction and activator of transcription; TNF-α, \n466 Tumor necrosis factor-α; TNF-α, Tumor necrosis factor-α; TXD, TianXiangDan; TXL, \n467 TongXinLuo; XQT, XiangQiTang.\n468 Table 3. Effects of CCM, CMM and MBC injury induced by inflammatory.\nCCM, \nCMM and \nMBC\nIn \nvitro/in \nvivo\nModel \n(cells) Model (animals) Signaling \npathways Effects Inflammatory \nmediators References\nTXD Both\nHuman \nCMECs \n(LPS)\nSD rats（Inject \nsodium laurate \nwas injected \ninto the left \nventricle）\nNrf2/HO-1 \nsignaling \npathway; NF-κB \nsignaling \npathway\n4;10; ↓IL-1β, ↓TNF-α Sawuer et \nal. (2021)\nQLQX In vitro\nHuman \nCMECs \n(Hcy)\n/\nJAK/STAT \nsignaling \npathway\n4;10; ↓IL-6 Zhang et al. \n(2019)\nTXL In vitro\nHuman \nCMECs \n(C16)\n/ NF-κB signaling \npathway 2;4; ↓IL-1β, ↓TNF-α, \n↓MDA, ↓SOD\nWu et al. \n(2015)\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 27 / 58\nSA In vitro\nRat \nCMECs \n(TNF-α)\n/\nMAPK signaling \npathway; NF-κB \nsignaingl \npathway\n4;5;\n↓VCAM-1, ↓IL-\n1β, ↓IL-6, ↓MCP-\n1\nLi et al. \n(2019)\n4-ACGC Both\nRat \nCMECs \n(TNF-α)\nSD male rats \n(Left anterior \ndescending \ncoronary \nligation）\n/ 4; ↓IL-1β, ↓IL-6 Yang et al. \n(2018)\nSMF In vitro\nRat \nCMECs \n(LPS)\n/ NF-κB signaling \npathway 4;5;\n↓IL-1, ↓IL-6, \n↓TNF-α, ↓ICAM-\n1, ↓LDH\nZhu et al. \n(2017)\nCYT Both\nRat \nCMECs \n(LPS)\nSD male rats \n(Left anterior \ndescending \ncoronary \nligation）\nNF-κB signaling \npathway 4; ↓TNF-α, ↓IL-1β, \n↓IL-6\nYang et al. \n(2017)\nAND In vitro\nRat \nCMECs \n(LPS)\n/ / 1;4; ↓IL-6, ↓TNF-α Feng et al. \n(2017)\nIn vitro\nRat \nCMECs \n(LPS)\n/\nMAPK signaling \npathway; \nKLF2mRNA/NF-\nκB signaling \npathway\n4;5;13; ↓TNF-α, ↓ICAM-\n1, ↓PAI-1\nHe et al. \n(2013)\nCYP In vitro\nRat \nCMECs \n(LPS)\n/\nMAPK signaling \npathway; \nKLF2mRNA/NF-\nκB signaling \npathway\n4;5;13; ↓TNF-α, ↓ICAM-\n1, ↓PAI-1\nHe et al. \n(2013)\nXQT In vitro\nRat \nCMECs \n(LPS)\n/\nMAPK signaling \npathway; \nKLF2mRNA/NF-\nκB signaling \npathway\n4;5;13; ↓TNF-α, ↓ICAM-\n1, ↓PAI-1\nHe et al. \n(2013)\nASIV In vitro\nRat \nCMECs \n(LPS)\n/\nMAPK signaling \npathway; \nKLF2mRNA/NF-\nkB signaling \npathway\n4;5;13; ↓TNF-α, ↓ICAM-\n1, ↓PAI-1\nHe et al. \n(2013)\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 28 / 58\nBTE In vitro\nHuman \nCMECs \n(IL-1β)\n/ / 4; ↓IL-6 Lakota et al. \n(2009)\nRSV In vitro\nHuman \nCMECs \n(IL-1β)\n/ / 4; ↓IL-6, \n↓prostacyclin\nLakota et al. \n(2009)\n469 4-ACGC, 4-O-(2″-O-acetyl-6″-O- p-coumaroyl-β-D-glucopyranosyl) -p-coumaric acid; AND, \n470 Andrographolide; ASIV, Astragaloside IV; BTE, Black tea extract; CCM, Compound \n471 Chinese medicine; CMECs, Cardiac microvascular endothelial cells; CMM, Chinese \n472 materia medica; CYP, Alpha-Cyperone; CYT, Caffeoylxanthiazonoside; Hcy, \n473 Homocysteine; HO-1, Heme oxygenase-1; ICAM, Intercellular cell adhesion molecule; IL, \n474 Interleukin; JAK, Janus tyrosine kinase; KLF, Krüppel-like factor; LDH, Lactate \n475 dehydrogenase; LPS, lipopolysaccharide; MAPK, Mitogen-activated protein kinase; MBC, \n476 Major bioactive component; MDA, Malondialdehyde; NF-κB, Nuclear factor-kappa B; Nrf2, \n477 Nuclear factor‑erythroid 2 related factor 2; PAI, Plasminogen activator inhibitor; QLQX, \n478 QiLiQiangXin; RSV, Resveratrol; SA, Salidroside; SD, Sprague Dawley; SMF, ShenMai \n479 formula; SOD, Superoxide Dismutase; STAT, Signal transduction and activator of \n480 transcription; TNF-α, Tumor necrosis factor α; TXD, TianXiangDan; TXL, TongXinLuo; \n481 XQT, XiangQiTang; 1, Regulation of energy metabolism; 2, Attenuation of oxidative stress; \n482 3, Anti-apoptosis; 4, Inhibition of inflammatory cytokines release; 5, Regulation of adhesion \n483 molecule expression; 6, Alleviation microvascular hyperpermeability; 7, Repression \n484 autophagy; 8, Inhibition of fibrosis; 9, Controlling both paracrine and autocrine processes; \n485 10, Promotion of microvascular generation; 11, Dilation of coronary microvessels; 12, Cell \n486 senescence mitigation; 13, Reducing potential microthrombosis; 14, Anti-pyroptosis; 15, \n487 Improving the structure of the cell.\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 29 / 58\n488\n489 The inhibitory effect of TianXiangDan (TXD) on LPS-induced microvascular \n490 endothelial inflammation has been associated with the activation of nuclear factor-erythroid \n491 2-related factor 2 (Nrf2). Heme oxygenase-1 (HO-1) is one of the downstream proteins in \n492 the Nrf2 signaling pathway. TXD exerts its anti-inflammatory effects by suppressing the \n493 expression of TNF-α, phosphorylated inhibitor of kappa B alpha (p-IκBα), phosphorylated \n494 p65 (p-p65), and interleukin (IL)-1β through the induction of HO-1 protein [83].\n495 C16 induction in cells leads to oxidative stress and inflammation. Among the various \n496 sources of intracellular ROS, Nicotinamide adenine dinucleotide phosphate (NADPH) \n497 oxidase plays a significant role [84, 85]. TXL inhibits the release of TNF-α and IL-1β \n498 induced by C16 through the blockade of NF-κB activation and expression. Moreover, TXL \n499 suppresses the upregulation of malondialdehyde (MDA) and superoxide dismutase (SOD), \n500 thereby reducing the production of ROS. Its antioxidant activities may be attributed to the \n501 suppression of HO-1 and NADPH oxidase complex expression in human CMECs [86].\n502 Different levels of NF-κB p65 expression and regulation are observed in the cytoplasm \n503 and nucleus. When exposed to LPS, the fruit of Xanthium strumarium L plant contains an \n504 active ingredient called caffeoylxanthiazonoside (CYT), which significantly reduces the \n505 production of TNF-α, IL-1β, and IL-6. Additionally, there is an upregulation of inhibitor of \n506 NF-κB (IκB）and cytoplasmic NF-κB p65 protein expression, along with a downregulation \n507 of nuclear NF-κB p65 [87]. \n508 Inflammation and coagulation are closely related and can mutually promote each other \n509 [88]. Plasminogen activator inhibitor (PAI)-1 [89] and tissue factor (TF) [90] are important \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 30 / 58\n510 factors in the coagulation cascade. XiangQiTang (XQT) and its components, Alpha-\n511 Cyperone (CYP), ASIV, and andrographolide (AND), inhibit LPS-stimulated production of \n512 TNF-α, intercellular adhesion molecule-1, and PAI-1. They also upregulate KLF2 mRNA \n513 expression, reduce the phosphorylation level of NF-κB p65 protein, and inhibit TF secretion. \n514 Moreover, XQT, CYP, ASIV, and AND suppress the expression of proteins involved in the \n515 MAPK signaling pathway [91]. \n516 Caveolin-1 is a crucial structural protein that facilitates the transmembrane transport \n517 of low-density lipoprotein cholesterol (LDL-C), thereby promoting the development of \n518 atherosclerosis [92]. AND significantly reduces caveolin-1 expression in LPS-induced \n519 CMECs. It modulates the expression of IL-6 and TNF-α among inflammatory factors and \n520 inhibits extracellular ATP-induced calcium release by decreasing the expression of \n521 phospholipase Cδ3 (PLCδ3), without affecting extracellular calcium endocytosis. This has \n522 a limited impact on nitric oxide (NO) production and release [93].\n523 Lakota et al.[94] demonstrated that human CMECs responded dose-dependently to \n524 IL-1β-induced IL-6 levels and prostacyclin release. The administration of black tea extract \n525 (BTE) and RSV inhibited IL-1β-induced responses. Additionally, QLQX downregulated the \n526 expression of phosphorylated STAT3, phosphorylated JAK2, and IL-6 in CMECs. It \n527 upregulated the expression of vascular-endothelial growth factor A (VEGFA), mitigated the \n528 inflammatory process induced by Hcy, and promoted angiogenesis, potentially through \n529 modulation of the JAK/STAT signaling pathway [95].\n530 3.4. TCM that Modify CMECs in Metabolic Injury Model\n531 Cellular metabolism is essential for maintaining normal cellular biochemical processes \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 31 / 58\n532 and biological activities. Patients with metabolic abnormalities, such as elevated levels of \n533 free fatty acids and chronic hyperglycemia, face an augmented risk of cardiovascular \n534 events [96].\n535 A high fat diet (HFD) is a significant risk factor for organ damage, including the liver, \n536 kidneys, and heart, leading to increased mortality [97]. HFD can induce capillary \n537 permeability in the microvascular environment, potentially leading to interstitial fibrosis and \n538 myocardial dysfunction [98]. In mice fed a HFD, chronic intermittent administration of \n539 quercetin (Q) reduces intramyocardial fat accumulation, increases cardiac microvessel \n540 density, and regulates oxidative stress [99]. \n541 Apolipoprotein E (apoE) deficiency is known to cause elevated levels of cholesterol-\n542 rich compounds in the bloodstream, contributing to the development of atherosclerotic \n543 lesions [100]. Treatment with TXL significantly decreases lipid levels, reduces \n544 atherosclerotic plaque formation in apoE-deficient mice, and improves endothelial cell \n545 function [86]. \n546 In animal models, N(ω)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase \n547 (NOS) inhibitor, suppresses NOS activity and reduces NO production, leading to increased \n548 blood pressure and the progression of left ventricular remodeling [101]. QSYQ has been \n549 found to increase myocardial capillary density and inhibit microvascular endothelial \n550 inflammation induced by L-NAME combined with the HFD [102].\n551 A high glucose (HG) environment can downregulate the expression of claudins-5 and \n552 -11 in human CMECs. TXL can reverse the HG-induced inhibition of claudins-5 and -11 by \n553 increasing H3K9ac in the promoters of these genes. Moreover, high-dose TXL treatment \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 32 / 58\n554 promotes the membrane localization of claudins-5 and -11 in HG-stimulated human \n555 CMECs [103]. \n556 Angiopoietin-like 4 (Angptl4) plays a protective role in regulating the endothelial barrier, \n557 maintaining vascular integrity by preserving the VE-calmodulin complex [104]. In the \n558 context of preserving the structure and function of the endothelial barrier under conditions \n559 of high glucose-induced I/R, TXL has been found to be comparable to insulin and \n560 recombinant human Angptl4. The expression of Angptl4 can be induced by peroxisome \n561 proliferator-activated receptor α (PPAR-α). In diabetic patients, TXL may preserve the \n562 integrity of the endothelial barrier against I/R injury through the activation of the PPAR-\n563 α/Angptl4 signaling pathway [105, 106].\n564 3.5. TCM that Modify CMECs in Ang II Injury Model\n565 Ang II is a bioactive peptide that regulates vascular tone and promotes the proliferation \n566 of vascular smooth muscle cells, playing a pivotal role in the pathogenesis of \n567 cardiovascular disease. Ang II has been implicated in inducing cardiac hypertrophy [107], \n568 a which is an independent risk factor for mortality [108]. Studies have found that Ang II-\n569 induced apoptosis in CMECs is closely associated with the development of CMD in heart \n570 failure patients [109]. It has been observed that Ang II enhances endothelial cell apoptosis, \n571 impairs the shear response of CMECs, and hampers the morphological adaptation to shear \n572 stress by downregulating the expression of platelet-endothelial cell adhesion molecule-1 \n573 (PECAM-1). Allicin (A), through stimulation of the PECAM-1/PI3K/AKT/eNOS signaling \n574 pathway, downregulation of caspase-3 and receptor interacting protein 3 (RIP3) \n575 expression, and prevention of necrotic apoptosis, enhances the functionality of CMECs. A \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 33 / 58\n576 was found to increase microvessel density in rats with cardiac hypertrophy induced by \n577 abdominal aortic constriction [110].\n578 Autophagy is a cyclic process involved in maintaining cellular homeostasis [111]. The \n579 Forkhead-Box Class O (FoxO) family member, FoxO3a, regulates autophagy by activating \n580 genes involved in autophagosome formation [112]. CMECs exposed to Ang II undergo \n581 apoptosis, but QLQX prevents this by inhibiting autophagy through the ErbB2/AKT/FoxO3a \n582 signaling pathway [113]. In terms of the microvascular endothelial barrier, TXL attenuates \n583 the damage to human CMECs induced by Ang II by promoting KLF5 expression, which \n584 enhances the levels of tight junction proteins [114].\n585 3.6. TCM that Modify CMECs in Other Injury Models\n586 Aging is considered an independent factor associated with endothelial cell dysfunction \n587 [115]. TCM has shown promise in alleviating senescence in CMECs. From a cytoskeletal \n588 perspective, age affects the structure and function of F-actin. Extracts of Panax \n589 Notoginseng (PN), Radix Ginseng (RG), and Rhizoma Ligustici Chuanxiong (RLC) have \n590 been found to delay the senescence of CMECs in response to heat shock protein 27 \n591 (HSP27) and reduce F-actin synthesis [116]. \n592 Viral myocarditis (VMC) is a common cardiovascular disease [117]. Chronic phase \n593 VMC is characterized by MF [118]. CFs are the most affected cells in MF [119]. It has been \n594 discovered that CFs can also arise from the EndMT process, which may contribute to MF \n595 development in VMC [120]. Ginsenoside-Rb3 (Rb3), a major component of Sanqi and \n596 Renshen, inhibits EndMT in CMECs after coxsackievirus B3 (CVB3) infection through the \n597 proline-rich tyrosine kinase (Pyk) 2/PI3K/AKT signaling pathway [121]. Ginsenoside-Rg3 \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 34 / 58\n598 (Rg3) activates AKT to upregulate the Nrf2/antioxidant response element (ARE) pathway, \n599 thereby mitigating cardiotoxicity caused by adriamycin (ADM) and ameliorating endothelial \n600 dysfunction resulting from oxidative stress [122]. Millettia pulchra Kurz var.laxior (Dunn) Z. \n601 Wei is a wild plant from the Fabaceae family with diverse therapeutic uses. Its root contains \n602 the flavonoid monomer 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) [123]. In \n603 an animal model, MHBFC attenuated L-NAME-induced apoptosis of CMECs during \n604 cardiac remodeling in rats [124]. Diosmetin-7-O-β-D-glucopyranoside (Diosmetin-7-O-\n605 glucoside) is a natural flavonoid abundant in citrus fruits and herbal extracts like fructus \n606 trichosanthes peel [125]. In primary CMECs, TGF-β1 promoted EndMT. Diosmetin-7-O-\n607 glucoside, partly through an Src-dependent mechanism, regulates EndMT via endoplasmic \n608 reticulum stress [126]. \n609 Some studies have focused on the direct intervention of Chinese medicine or active \n610 ingredients without specifically addressing CMEC injury. For instance, the chemical \n611 constituents of Ophiopogon japonicus (OJ) fiber root and DG were found to modulate \n612 angiogenesis in human CMECs, promoting microvessel formation [127, 128]. In terms of \n613 regulating microvascular function, long-term oral treatment with Oroxylin A (OA), the \n614 primary constituent of Radix Scutellariae (RS), was found to enhance the production of NO \n615 and the expression of eNOS protein in CMECs, as well as the production of NO and the \n616 expression of iNOS protein in vascular smooth muscle cells (VSMCs). It was proposed that \n617 the mechanism of action of OA involved the modulation of the estrogen receptor (ER) \n618 signaling pathway [129]. Tanshinone Ⅱ A (Tan Ⅱ A) was found to activate the ER \n619 signaling pathway in primary CMECs, leading to increased expression of eNOS gene, NO \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 35 / 58\n620 production, ERK1/2 phosphorylation, and Ca2+ mobilization [130]. In the treatment of heart \n621 failure (HF), periplocin (PER) in Cortex Periplocae Sepii Radicis was compared with the \n622 cardiac glycoside ouabain. PER was found to increase cell proliferation, reduce cell \n623 damage, inhibit apoptosis, and affect the expression of guanosine triphosphate (GTP)-\n624 binding proteins, which are closely related to intracellular calcium signaling. The underlying \n625 mechanism may involve the protein serine/threonine kinase pathway, cellular metabolism, \n626 and other cellular processes [131].\n627 4. Outlook for Future Research\n628 CMD poses a significant challenge to achieving clinical benefits in IHD, and effective \n629 interventions are currently limited, providing an opportunity for intervention with TCM. In \n630 recent years, several studies have demonstrated that TCM can improve CMD by protecting \n631 CMECs against various injuries. These interventions have shown structural improvements \n632 such as increased microvessel density and number, reduced microthrombosis, and \n633 inhibition of endothelial-to-mesenchymal transition. Functionally, TCM has been found to \n634 dilate coronary microvessels, alleviate microvascular permeability, and delay cellular \n635 senescence in CMECs. The mechanisms of action involve antioxidant, anti-apoptotic, anti-\n636 inflammatory effects, as well as regulation of energy metabolism, among others.\n637 Considering that disease manifestation is often the result of multiple cell types within \n638 the same tissue or involving other tissues, co-culture systems have been used to mimic \n639 this condition, where different cell types share the same culture environment [132]. Recent \n640 studies have highlighted the ability of TCM to modulate the paracrine and autocrine \n641 secretion of CMECs, thereby influencing their own behavior and that of surrounding cells. \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 36 / 58\n642 Enhancing the crosstalk between different cell types represents an important area for \n643 future research. Additionally, it has been observed that women have a higher risk of CMD \n644 compared to men [133], emphasizing the importance of studying gender differences in the \n645 pathophysiology of CMD [134]. Currently, preclinical studies rarely consider gender as a \n646 variable in their analyses [135]. Therefore, investigating the effects of CMD on CMECs in \n647 different genders may present a new research direction.\n648 5. Limitations\n649 The present study has several limitations that should be acknowledged. Firstly, the \n650 specific chemical structures of the active ingredients present in the Chinese medicines \n651 discussed in some articles remain unknown. Secondly, there are variations in the \n652 intervention methods used for compound Chinese medicines or the core components of \n653 Chinese medicines across different studies, leading to variations in the observed effects. \n654 Therefore, it is still necessary to establish standardized and uniform intervention methods \n655 to ensure consistency and comparability among studies.\n656 6. Summary\n657 This systematic review provides evidence that different injury models lead to distinct \n658 phenotypes in CMECs, and the intervention mechanisms of TCM also vary accordingly. \n659 Specifically, under ischemic or hypoxic injury conditions, TCM demonstrates its efficacy by \n660 promoting microangiogenesis, alleviating microvascular permeability, and inhibiting \n661 myocardial fibrosis. These effects are mediated through signaling pathways such as HIF-\n662 1α/VEGF, PI3K/AKT, and Snail. In the context of H/R injury, TCM exerts its benefits by \n663 inhibiting apoptosis, alleviating microvascular permeability, and dilating coronary \n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 37 / 58\n664 microvessels, involving pathways such as ATM, PI3K/AKT, p70s6kT, p70s6kT/eNOS, and \n665 others. In the case of inflammatory injury, TCM acts by suppressing the release of \n666 inflammatory cytokines, regulating the expression of adhesion molecules, and reducing the \n667 formation of microthrombosis, through pathways such as MAPK, NF-κB, and JAK/STAT. \n668 Furthermore, under metabolic injury, angiotensin II, aging, and other pathological \n669 conditions, TCM demonstrates its efficacy by alleviating microvascular permeability, \n670 dilating coronary microvessels, and inhibiting inflammation and oxidative stress. The \n671 underlying signaling pathways involved include PPAR-α/Angptl4, H3K9ac/claudins, \n672 PI3K/AKT, among others. This systematic review provides a comprehensive overview of \n673 the effects of TCM on CMECs in various injury models and highlights the associated \n674 signaling pathway studies. These findings serve as a foundation for the application of TCM \n675 in the treatment of CMD.\n676 Acknowledgments\n677 The authors would like to thank those who provided comments on the revision of this \n678 review.\n679\n680 References \n681 1. Chen W, Ni M, Huang H, Cong H, Fu X, Gao W, et al. Chinese expert consensus on \n682 the diagnosis and treatment of coronary microvascular diseases (2023 Edition). \n683 MedComm (2020). 2023;4(6):e438. pmid:38116064 \n684 2. Del Buono MG, Montone RA, Camilli M, Carbone S, Narula J, Lavie CJ, et al. Coronary \n685 Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: \n.CC-BY 4.0 International licenseperpetuity. 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It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n 58 / 58\n1126\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseperpetuity. It is made available under a \npreprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in \nThe copyright holder for thisthis version posted September 8, 2024. ; https://doi.org/10.1101/2024.09.05.611361doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseperpetuity. 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