Zhao Wen-Jing, Qian Yi, Zhang Yi-Feng, Yang Ai-Hua, Cao Jia-Xin, Qian Hong-Yan, Liu Yi, Zhu Wei-Zhong
Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, 226001, China.
Cancer Research Center Nantong, Nantong Tumor Hospital and Tumor Hospital Affiliated to Nantong University, Nantong, 226006, China.
Acta Pharmacol Sin. 2025 Apr;46(4):922-939. doi: 10.1038/s41401-024-01410-9. Epub 2024 Nov 26.
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.
血管重塑是心肌病变（包括心肌肥大和心肌梗死）的病理基础，最终可导致心力衰竭。心肌梗死再灌注后，血管紧张素II（Ang II）诱导血管重塑的分子机制复杂，尚未完全阐明。在本研究中，我们检测了Ang II输注对小鼠心脏血管重塑的影响。单细胞测序显示，Ang II可诱导细胞骨架途径富集，通过拟时间分析表明FOS样蛋白1（FOSL1）影响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。血管紧张素II 1型受体阻滞剂替米沙坦和蛋白激酶C抑制剂星形孢菌素可抑制Ang II诱导的人脐静脉内皮细胞中MYH9的上调和FOSL1磷酸化。沉默MYH9可消除Ang II介导的人脐静脉内皮细胞血管生成抑制，并减轻Ang II诱导的血管通透性增加。我们发现FOSL1直接与MYH9启动子结合，从而通过双荧光素酶报告基因和染色质免疫沉淀试验激活MYH9转录，导致血管功能障碍。在体内，注射携带TEK酪氨酸激酶（tie）启动子驱动的短发夹RNA以沉默FOSL1的腺相关病毒-ENT（AAV-tie-shFOSL1）6周后，以射血分数和缩短分数表示的心脏功能得到改善，心肌纤维化减轻，磷酸化FOSL1、MYH9和I型胶原蛋白α的蛋白水平降低，Ang II输注小鼠中内皮Fosl1特异性敲低的小鼠心脏血管密度恢复。在缺血再灌注小鼠中，与对照AAV小鼠相比，AAV-shFosl1小鼠梗死面积减小，心脏功能得以保留。我们的研究结果表明FOSL1/MYH9轴在阻碍Ang II诱导的血管重塑中起关键作用，并且我们确定FOSL1是心肌缺血再灌注诱导的内皮细胞损伤的潜在治疗靶点。
