Endothelial FOSL1 drives angiotensin Ⅱ-induced myocardial injury via AT1R-upregulated MYH9  

作　　者：Wen-jing Zhao Yi Qian Yi-feng Zhang Ai-hua Yang Jia-xin Cao Hong-yan Qian Yi Liu Wei-zhong Zhu 

机构地区：[1]Department of Pharmacology,School of Medicine and School of Pharmacy Nantong University,Nantong,226001,China [2]Cancer Research Center Nantong,Nantong Tumor Hospital and Tumor Hospital Affiliated to Nantong University,Nantong,226006,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期922-939,共18页中国药理学报(英文版)

基　　金：funded by grants(82102784 and 81770440)from the National Natural Science Foundation of China;funded by Health Committee of Nantong(MS2023055 and MSZ2023041);Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_3440).

摘　　要：Vascular remodeling represents a pathological basis for myocardial pathologies,including myocardial hypertrophy and myocardial infarction,which can ultimately lead to heart failure.The molecular mechanism of angiotensin Ⅱ(AngⅡ)-induced vascular remodeling following myocardial infarction reperfusion is complex and not yet fully understood.In this study,we examined the effect of Ang Ⅱ infusion on cardiac vascular remodeling in mice.Single-cell sequencing showed Ang Ⅱ induced cytoskeletal pathway enrichment and that FOS like-1(FOSL1)affected mouse cardiac endothelial dysfunction by pseudotime analysis.Myosin heavy chain 9(MYH9)was predominantly expressed in primary cardiac endothelial cells.The Ang Ⅱ type Ⅰ receptor blocker telmisartan and the protein kinase C inhibitor staurosporine suppressed Ang Ⅱ-induced upregulation of MYH9 and FOSL1 phosphorylation in human umbilical vein endothelial cells.Silencing MYH9 abolished Ang Ⅱ-mediated inhibition of angiogenesis in human umbilical vein endothelial cells,and attenuated Ang Ⅱ-induced vascular hyperpermeability.We found that FOSL1 directly bound to the MYH9 promoter and thus activated transcription of MYH9 by the dual luciferase reporter and chromatin immunoprecipitation assays,leading to vascular dysfunction.In vivo,6 weeks after injecting adeno-associated virus-ENT carrying the TEK tyrosine kinase(tie)promoter-driven short hairpin RNA for silencing FOSL1(AAV-tie-shFOSL1),cardiac function represented by the ejection fraction and fractional shortening was improved,myocardial fibrosis was decreased,protein levels of phosphorylated FOSL1,MYH9,and collagen type Ⅰ alpha were reduced,and cardiac vascular density was recovered in mice with endothelial Fosl1-specific knockdown in Ang Ⅱ-infused mice.In ischemia-reperfusion mice,AAV-shFosl1 mice had a reduced infarct size and preserved cardiac function compared with control AAV mice.Our findings suggest a critical role of the FOSL1/MYH9 axis in hindering Ang Ⅱ-induced vascular remodeling,and we identified

关 键 词：angiotensinⅡ myocardial ischemia-reperfusion FOS like-1(FOSL1) myosin heavy chain 9(MYH9) endothelial cell transcription activation 

分 类 号：R54[医药卫生—心血管疾病]