南通大学朱卫忠研究小组发现，内皮FOSL1通过AT1R上调MYH9驱动血管紧张素II引起的心肌损伤。相关论文于2024年11月26日在线发表在《中国药理学报》杂志上。

研究人员探讨了血管紧张素II（Ang II）注射对小鼠心脏血管重塑的影响。单细胞测序显示，Ang II诱导了细胞骨架通路的富集，且FOS样-1（FOSL1）通过伪时间分析影响了小鼠心脏内皮功能障碍。肌球蛋白重链9（MYH9）主要在原代心脏内皮细胞中表达。Ang II类型I受体拮抗剂替米沙坦和蛋白激酶C抑制剂Staurosporine抑制了Ang II诱导的MYH9上调和FOSL1磷酸化在人脐静脉内皮细胞中的作用。沉默MYH9消除了Ang II介导的人脐静脉内皮细胞的血管生成抑制作用，并减轻了Ang II引起的血管高通透性。

研究人员发现FOSL1直接与MYH9启动子结合，通过双荧光素酶报告基因和染色质免疫沉淀实验激活MYH9转录，导致血管功能障碍。在体内，6周后注射载有TEK酪氨酸激酶（tie）启动子驱动的短发夹RNA沉默FOSL1（AAV-tie-shFOSL1）的小鼠，其射血分数和分数缩短代表的心脏功能得到改善，心肌纤维化减少，磷酸化FOSL1、MYH9和I型胶原蛋白的蛋白水平降低，心脏血管密度恢复。在缺血再灌注小鼠中，与对照AAV小鼠相比，AAV-shFosl1小鼠的梗死面积减少，心脏功能得以保持。

该研究发现FOSL1/MYH9轴在阻碍Ang II引起的血管重塑中起着关键作用，并将FOSL1确定为心肌缺血再灌注引起的内皮细胞损伤的潜在治疗靶点。

据了解，血管重塑是心肌病理的病理基础，包括心肌肥厚和心肌梗死，最终可能导致心力衰竭。Ang II引起的心肌梗死后血管重塑的分子机制复杂，尚未完全理解。

附：英文原文

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

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

Issue&Volume: 2024-11-26

Abstract: 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 (Ang II)-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 AngII-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 FOSL1 as a potential therapeutic target in endothelial cell injuries induced by myocardial ischemia-reperfusion.

DOI: 10.1038/s41401-024-01410-9

Source: https://www.nature.com/articles/s41401-024-01410-9