Ullah Karim, Ai Lizhuo, Li Yan, Liu Lifeng, Zhang Qin, Pan Kaichao, Humayun Zainab, Piao Lin, Sitikov Albert, Su Qiaozhu, Zhao Qiong, Sharp Willard, Fang Yun, Wu David, Liao James K, Wu Rongxue
bioRxiv. 2024 Apr 27:2023.03.12.532316. doi: 10.1101/2023.03.12.532316.
Myocardial infarction (MI) significantly compromises the integrity of the cardiac microvascular endothelial barrier, leading to enhanced leakage and inflammation that contribute to the progression of heart failure. While HIF2α is highly expressed in cardiac endothelial cells (ECs) under hypoxic conditions, its role in regulating microvascular endothelial barrier function during MI is not well understood. In this study, we utilized mice with a cardiac-specific deletion of HIF2α, generated through an inducible Cre (Cdh5Cre-ERT2) recombinase system. These mice exhibited no apparent phenotype under normal conditions. However, following left anterior descending (LAD) artery ligation-induced MI, they showed increased mortality associated with enhanced cardiac vascular leakage, inflammation, worsened cardiac function, and exacerbated heart remodeling. These outcomes suggest a protective role for endothelial HIF2α in response to cardiac ischemia. Parallel investigations in human cardiac microvascular endothelial cells (CMVECs) revealed that loss of ecHif2α led to diminished endothelial barrier function, characterized by reduced tight-junction protein levels and increased cell death, along with elevated expression of IL6 and other inflammatory markers. These effects were substantially reversed by overexpressing ARNT, a critical dimerization partner for HIF2α during hypoxia. Additionally, ARNT deletion also led to increased CMVEC permeability. Interestingly, ARNT, rather than HIF2α itself, directly binds to the IL6 promoter to suppress IL6 expression. Our findings demonstrate the critical role of endothelial HIF2α in response to MI and identify the HIF2α/ARNT axis as a transcriptional repressor, offering novel insights for developing therapeutic strategies against heart failure following MI.
心肌梗死（MI）显著损害心脏微血管内皮屏障的完整性，导致渗漏增加和炎症反应，促进心力衰竭的进展。虽然缺氧条件下HIF2α在心脏内皮细胞（ECs）中高表达，但其在心肌梗死期间调节微血管内皮屏障功能中的作用尚未完全明确。在本研究中，我们利用通过诱导型Cre（Cdh5Cre-ERT2）重组酶系统构建的心脏特异性缺失HIF2α的小鼠。这些小鼠在正常条件下没有明显的表型。然而，在左前降支（LAD）动脉结扎诱导的心肌梗死后，它们的死亡率增加，伴有心脏血管渗漏增加、炎症反应、心脏功能恶化和心脏重塑加剧。这些结果表明内皮HIF2α在应对心脏缺血时具有保护作用。对人心脏微血管内皮细胞（CMVECs）的平行研究表明，ecHif2α缺失导致内皮屏障功能减弱，表现为紧密连接蛋白水平降低和细胞死亡增加，以及IL6和其他炎症标志物表达升高。过表达ARNT可显著逆转这些效应，ARNT是缺氧期间HIF2α的关键二聚化伴侣。此外，ARNT缺失也导致CMVEC通透性增加。有趣的是，直接与IL6启动子结合以抑制IL6表达的是ARNT，而非HIF2α本身。我们的研究结果证明了内皮HIF2α在应对心肌梗死中的关键作用，并确定HIF2α/ARNT轴为转录抑制因子，为开发心肌梗死后心力衰竭的治疗策略提供了新的见解。
