From the Vascular Biology and Therapeutics Program (X.Z., C.M.R., B.A., Y.S., W.C.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.
Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology (X.Z., C.M.R., B.A., Y.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.
Arterioscler Thromb Vasc Biol. 2020 Jun;40(6):1510-1522. doi: 10.1161/ATVBAHA.120.314291. Epub 2020 Apr 30.
Endothelial Cav-1 (caveolin-1) expression plays a relevant role during atherogenesis by controlling NO production, vascular inflammation, LDL (low-density lipoprotein) transcytosis, and extracellular matrix remodeling. Additional studies have identified cholesterol-rich membrane domains as important regulators of autophagy by recruiting ATGs (autophagy-related proteins) to the plasma membrane. Here, we investigate how the expression of Cav-1 in the aortic endothelium influences autophagy and whether enhanced autophagy contributes to the atheroprotective phenotype observed in Cav-1-deficient mice. Approach and Results: To analyze the impact of Cav-1 deficiency on regulation of autophagy in the aortic endothelium during the progression of atherosclerosis, we fed and mice a Western diet and assessed autophagy in the vasculature. We observe that the absence of Cav-1 promotes autophagy activation in athero-prone areas of the aortic endothelium by enhancing autophagic flux. Mechanistically, we found that Cav-1 interacts with the ATG5-ATG12 complex and influences the cellular localization of autophagosome components in lipid rafts, which controls the autophagosome formation and autophagic flux. Pharmacological inhibition of autophagy attenuates the atheroprotection observed in mice by increasing endothelial inflammation and macrophage recruitment, identifying a novel molecular mechanism by which Cav-1 deficiency protects against the progression of atherosclerosis.
These results identify Cav-1 as a relevant regulator of autophagy in the aortic endothelium and demonstrate that pharmacological suppression of autophagic flux in Cav-1-deficient mice attenuates the atheroprotection observed in mice. Additionally, these findings suggest that activation of endothelial autophagy by blocking Cav-1 might provide a potential therapeutic strategy for cardiovascular diseases including atherosclerosis.
内皮细胞 Cav-1（窖蛋白-1）的表达通过控制一氧化氮（NO）的产生、血管炎症、LDL（低密度脂蛋白）的转胞吞作用以及细胞外基质重塑，在动脉粥样硬化形成过程中发挥重要作用。此外，研究还发现富含胆固醇的膜结构域可通过将 ATG（自噬相关蛋白）募集到质膜上来作为自噬的重要调节因子。在这里，我们研究了主动脉内皮细胞中 Cav-1 的表达如何影响自噬，以及增强的自噬是否有助于 Cav-1 缺陷型小鼠中观察到的抗动脉粥样硬化表型。
为了分析 Cav-1 缺陷对动脉粥样硬化进展过程中主动脉内皮细胞自噬调节的影响，我们用西方饮食喂养 和 小鼠，并评估了血管中的自噬作用。我们发现，Cav-1 的缺失通过增强自噬流，促进动脉粥样硬化易感区主动脉内皮细胞中的自噬激活。从机制上讲，我们发现 Cav-1 与 ATG5-ATG12 复合物相互作用，并影响脂筏中自噬体成分的细胞定位，从而控制自噬体的形成和自噬流。自噬的药理学抑制通过增加内皮炎症和巨噬细胞募集，加剧了 小鼠中的动脉粥样硬化保护作用，从而确定了 Cav-1 缺失保护动脉粥样硬化进展的新分子机制。
这些结果确定 Cav-1 是主动脉内皮细胞自噬的重要调节因子，并证明 Cav-1 缺陷型小鼠中自噬流的药理学抑制减弱了 小鼠中观察到的动脉粥样硬化保护作用。此外，这些发现表明通过阻断 Cav-1 激活内皮自噬可能为包括动脉粥样硬化在内的心血管疾病提供一种潜在的治疗策略。
