Interleukin-5 deficiency promotes macrophage differentiation and exacerbates cardiac remodeling via the STAT3 pathway in angiotensin II-infused mice Running title: IL-5 alleviates cardiac remodeling

Interleukin-5 (IL-5) was reported to participate in cardiovascular diseases, this study aimed to investigate the effects of IL-5 on cardiac remodeling. Mice were infused with angiotensin II (Ang II), and we found cardiac IL-5 expression was time- and dose-dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, the effects of IL-5 knockout on Ang II-induced cardiac remodeling were observed, and the results exhibited that IL-5 deficiency significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross-sectional areas, and worsened cardiac dysfunction in Ang II-infused mice. IL-5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Effects of IL-5 on cardiac remodeling and M2 macrophage differentiation were reversed by S31-201. IL-5 knockout significantly increased the Ang II-induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co-cultured with macrophages, and this effect was also reversed by S31-201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co-cultured. Our study suggests that IL-5 deficiency promotes M2 macrophages differentiation and exacerbating cardiac remodeling by activating the STAT3 pathway in Ang II-infused mice. IL-5 may be a potential target for the clinical prevention of cardiac remodeling.