Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
Cell Signal. 2022 Oct;98:110410. doi: 10.1016/j.cellsig.2022.110410. Epub 2022 Jul 16.
ANGPTL4, a member of the angiopoietin-like protein family, is reported to be involved in angiogenesis regulation, lipid metabolism, glucose metabolism and redox reactions, among others. Our previous study showed that the plasma ANGPTL4 level was lower in coronary atherosclerotic heart disease (CAHD) and could be a useful predictor of coronary atherosclerosis. However, the molecular mechanism underlying the function of ANGPTL4 in atherosclerosis is poorly understood. In this study, we found that overexpression of ANGPTL4 in HUVECs enhanced cell proliferation and clone-forming ability in vitro, whereas knockdown of ANGPTL4 resulted in the opposite. The expression of ANGPTL4 was upregulated in palmitic acid (PA)-treated HUVECs. Overexpression of ANGPTL4 protected against PA-induced endothelial injury. Knockdown of ANGPTL4 exacerbated the effects of PA on HUVECs. Mechanistically, we demonstrated that ANGPTL4 promoted endothelial cell proliferation through the regulation of autophagy. Knockdown of ATG7 or 3-MA (an autophagy inhibitor) attenuated the effects of ANGPTL4 on endothelial cells. The serum level of ANGPTL4 was downregulated in atherosclerosis mice. Furthermore, the expression of ANGPTL4 was correlated with autophagy-related proteins in aortic tissues of atherosclerotic mice. ANGPTL4 promotes endothelial cell proliferation and suppresses PA-induced endothelial cell injury by increasing autophagy, which may protect against the development of atherosclerosis.
血管生成素样蛋白 4（ANGPTL4）是血管生成素样蛋白家族的成员，据报道其参与血管生成调节、脂质代谢、葡萄糖代谢和氧化还原反应等过程。我们之前的研究表明，血浆 ANGPTL4 水平在冠状动脉粥样硬化性心脏病（CAHD）中较低，可能是冠状动脉粥样硬化的有用预测指标。然而，ANGPTL4 在动脉粥样硬化中的功能的分子机制尚不清楚。在这项研究中，我们发现 HUVECs 中 ANGPTL4 的过表达增强了细胞的体外增殖和克隆形成能力，而 ANGPTL4 的敲低则产生了相反的效果。PA 处理的 HUVECs 中 ANGPTL4 的表达上调。ANGPTL4 的过表达可防止 PA 诱导的内皮损伤。ANGPTL4 的敲低加剧了 PA 对 HUVECs 的作用。在机制上，我们证明了 ANGPTL4 通过调节自噬促进内皮细胞增殖。ATG7 或 3-MA（自噬抑制剂）的敲低减弱了 ANGPTL4 对内皮细胞的作用。动脉粥样硬化小鼠的血清 ANGPTL4 水平下调。此外，动脉粥样硬化小鼠主动脉组织中 ANGPTL4 的表达与自噬相关蛋白相关。ANGPTL4 通过增加自噬促进内皮细胞增殖并抑制 PA 诱导的内皮细胞损伤，这可能有助于预防动脉粥样硬化的发生。
