Caveolin-1 Is a Critical Determinant of Autophagy, Metabolic Switching, and Oxidative Stress in Vascular Endothelium

Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1null mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1null mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H2O2. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.

窖蛋白-1（Caveolin-1）是一种可与多种信号分子相互作用的支架/调节蛋白。窖蛋白-1基因缺失小鼠存在显著的代谢异常，但其潜在分子机制尚未完全阐明。我们发现，血浆氧化应激生物标志物8-异前列腺素在窖蛋白-1缺失小鼠中水平升高；同时证实，在内皮细胞中通过小干扰RNA（siRNA）介导窖蛋白-1基因敲低，可显著提升细胞内过氧化氢（H₂O₂）水平。窖蛋白-1敲低后，内皮细胞的线粒体活性氧（ROS）生成量增加；2-脱氧-D-葡萄糖可抑制该效应，提示窖蛋白-1参与调控糖酵解通路。我们对窖蛋白-1敲低后的内皮细胞裂解物开展了无偏倚代谢组学分析，发现细胞内二肽水平显著升高（最高可达30倍），这与自噬激活的特征相符。代谢组学分析进一步显示，窖蛋白-1敲低会导致糖酵解中间产物水平降低，同时伴随脂肪酸水平升高，提示存在代谢转换现象。综上，上述研究结果证实，窖蛋白-1在内皮细胞的氧化应激调控、代谢转换及自噬过程中发挥核心作用，或可成为心血管疾病的关键干预靶点。