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by claude@2026-07, 2026-07-03
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The paper studied how abnormal shear stress affects endothelial cells by using a microfluidic device that generated three shear stress levels (low, medium, high) for 24 hours, assessing ferroptosis-related outcomes. Compared with medium shear, both low and high shear induced ferroptosis features, including increased lipid peroxidation and 4-hydroxynonenal, CoQ10 depletion, reduced SLC7A11 expression, and reduced cell death when treated with Ferrostatin-1; RNA-seq and Western blot further showed changes in cholesterol homeostasis, unfolded protein response signaling (PERK and BiP), and mevalonate pathway enzymes (MVD and IDI1). The authors used transcription-factor binding predictions to identify KLF6 as a key regulator linking PERK-mediated UPR and the mevalonate pathway to SLC7A11 and CoQ10, and reported that KLF6 overexpression restored these markers and reduced foam cell formation, monocyte adhesion, and lipid peroxidation under both low and high shear. A stated caveat is that the work focuses on endothelial cells under microfluidic shear conditions as a mechanistic model rather than testing in endogenously diseased human tissue. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Stable laminar flow maintains vascular tone regulation, while abnormal blood flow, such as disturbed flow or extreme shear stress, causes endothelial dysfunction, but the underlying mechanism is yet to be explored. We used a microfluidic device to deform flat microchannel into tunnel-like macrochannel. The cross-sectional area of this macrochannel varies with the flow rate and the thickness of the deformable layer, creating three levels of shear stress: low (0.99 dyn/cm 2 , LSS), medium (4.78 dyn/cm 2 , MSS), and high (24 dyn/cm 2 , HSS). Comparing different shear stress exposure to endothelial cells for 24 h, prominent ferroptosis features emerged under either LSS or HSS compared to MSS. These features included increased C11 BODIPY-labeled lipid peroxidation and 4-hydroxynonenal accumulation, CoQ10 depletion, reduced SLC7A11 protein expression, and diminished cell death with Ferrostatin-1 treatment. RNA-seq analysis (LSS/MSS) showed that LSS significantly downregulated transcription of cholesterol homeostasis and unfolded protein response (UPR). Compared to MSS, Western blot results showed that both LSS and HSS reduced the expression of two key enzymes (MVD and IDI1) in the mevalonate pathway, as well as the expression of two main UPR signaling regulators (PERK and BiP). Based on the binding prediction between transcription factors and gene promoters from differentially expressed genes identified through RNA-seq, we found KLF6 to be a key transcription factor. It regulates the PERK-mediated UPR and the mevalonate pathway, which are associated with SLC7A11 expression and CoQ10 synthesis, respectively. The overexpression of KLF6 restored SLC7A11 and CoQ10 levels under both LSS and HSS, significantly reducing foam cell formation, monocyte adhesion, and lipid peroxidation. Our findings reveal KLF6 as a crucial regulator of atherosclerosis induced by abnormal shear stress.
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Abstract
Stable laminar flow maintains vascular tone regulation, while abnormal blood flow, such as disturbed flow or extreme shear stress, causes endothelial dysfunction, but the underlying mechanism is yet to be explored. We used a microfluidic device to deform flat microchannel into tunnel-like macrochannel. The cross-sectional area of this macrochannel varies with the flow rate and the thickness of the deformable layer, creating three levels of shear stress: low (0.99 dyn/cm2, LSS), medium (4.78 dyn/cm2, MSS), and high (24 dyn/cm2, HSS). Comparing different shear stress exposure to endothelial cells for 24 h, prominent ferroptosis features emerged under either LSS or HSS compared to MSS. These features included increased C11 BODIPY-labeled lipid peroxidation and 4-hydroxynonenal accumulation, CoQ10 depletion, reduced SLC7A11 protein expression, and diminished cell death with Ferrostatin-1 treatment. RNA-seq analysis (LSS/MSS) showed that LSS significantly downregulated transcription of cholesterol homeostasis and unfolded protein response (UPR). Compared to MSS, Western blot results showed that both LSS and HSS reduced the expression of two key enzymes (MVD and IDI1) in the mevalonate pathway, as well as the expression of two main UPR signaling regulators (PERK and BiP). Based on the binding prediction between transcription factors and gene promoters from differentially expressed genes identified through RNA-seq, we found KLF6 to be a key transcription factor. It regulates the PERK-mediated UPR and the mevalonate pathway, which are associated with SLC7A11 expression and CoQ10 synthesis, respectively. The overexpression of KLF6 restored SLC7A11 and CoQ10 levels under both LSS and HSS, significantly reducing foam cell formation, monocyte adhesion, and lipid peroxidation. Our findings reveal KLF6 as a crucial regulator of atherosclerosis induced by abnormal shear stress.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
According to the reviewers' comments, the format and methods of the statistical graphs have been updated; in Figure 3F, the x-axis group 'LSS KLF6' has been changed to 'HSS KLF6'; the methods for chip cell culture and Fer-1 treatment have been added to the Materials and Methods section; all figures have been updated; the supplementary files include the original WB data and a link to the mRNA sequencing data.
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