PDF(Pubmed)
Abstract：
Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E\' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.
摘要：
内皮功能障碍是冠状动脉微血管疾病的早期事件。整合素连接激酶（ILK）防止内皮型一氧化氮合酶（eNOS）解偶联，因此，内皮功能障碍。然而,内皮ILK在心脏功能中的具体作用仍有待完全阐明。我们假设内皮ILK在维持冠状动脉微血管功能和心脏收缩性能中起着至关重要的作用。我们产生了内皮细胞特异性ILK条件性敲除小鼠（ecILKcKO），并研究了心血管功能。冠状动脉内皮ILK缺失显着损害心脏功能：射血分数，缩短分数和心输出量减少，左心室舒张内径减小，E/A和E/E比值增加，不仅表明收缩功能，也表明舒张功能不全。功能数据与广泛的细胞外基质重塑和血管周围纤维化相关，指示不良心脏重塑。具有内皮ILK缺失的小鼠出现早期缺血样事件,ST段抬高和一过性心肌肌钙蛋白增加,与纤维化重塑相关。此外,ecILKcKO小鼠表现出冠状动脉微血管疾病的许多特征：心脏灌注减少，心外膜冠状动脉未闭的冠状动脉血流储备和动脉重塑受损。此外，内皮ILK缺失导致血压适度升高，但抗高血压药物氯沙坦不影响微血管重塑,而仅部分改善纤维化重塑.血浆miRNA谱揭示了内皮至间充质转化(endMT)作为内皮ILK条件性KO小鼠中的上调途径。我们的结果表明，内皮ILK条件性KO小鼠的微血管中的内皮细胞经历了endMT。此外，从这些小鼠中分离的内皮细胞和ILK沉默的人微血管内皮细胞进行endMT，表明内皮ILK的降低直接导致了这种内皮表型的转变。我们的结果确定ILK是微血管内皮稳态的关键调节剂。内皮ILK预防微血管功能障碍和心脏重塑，有助于维持内皮细胞表型。
