Caveolin-1 (Cav-1) is a scaffolding protein and a major component of caveolae/lipid rafts. Previous reports have shown that endothelial dysfunction in Cav-1 deficient (Cav-1^-/-) mice is mediated by elevated oxidative stress through eNOS uncoupling and increased NADPH oxidase. Oxidant stress is the net balance of oxidant generation and scavenging and the role of Cav-1 as a regulator of antioxidant enzymes in vascular tissue is poorly understood. Extracellular SOD (SOD3) is a copper (Cu) containing enzyme that is secreted from vascular smooth muscle cells/fibroblasts and subsequently binds to the endothelial cells surface where it scavenges extracellular O₂^- and preserves endothelial function. SOD3 activity is dependent on Cu, supplied by the Cu transporter ATP7A, but whether Cav-1 regulates the ATP7A-SOD3 axis and its role in oxidative stress-mediated vascular dysfunction has not been studied. Here we show that the activity of SOD3, but not SOD1, was significantly decreased in Cav-1^-/- vessels, which was rescued by re-expression of Cav-1 or Cu supplementation. Loss of Cav-1 reduced ATP7A protein, but not mRNA, and this was mediated by ubiquitination of ATP7A and proteasomal degradation. ATP7A bound to Cav-1 and was co-localized with SOD3 in caveolae/lipid rafts or perinucleus in vascular tissues or cells. Impaired endothelium-dependent vasorelaxation in Cav-1^-/- mice was rescued by gene transfer of SOD3 or by ATP7A overexpressing transgenic mice. These data reveal an unexpected role of Cav-1 in stabilizing ATP7A protein expression by preventing its ubiquitination and proteasomal degradation, thereby increasing SOD3 activity, which in turn protects against vascular oxidative stress-mediated endothelial dysfunction.

中文翻译：

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Caveolin-1 可稳定血管组织中的 ATP7A（细胞外 SOD 的铜转运蛋白）以维持内皮功能。


Caveolin-1 (Cav-1) 是一种支架蛋白，也是小窝/脂筏的主要成分。先前的报告表明，Cav-1 缺陷 (Cav-1 ^-/- ) 小鼠的内皮功能障碍是由 eNOS 解偶联和 NADPH 氧化酶增加导致的氧化应激升高介导的。氧化应激是氧化剂产生和清除的净平衡，而 Cav-1 作为血管组织中抗氧化酶调节剂的作用尚不清楚。细胞外 SOD (SOD3) 是一种含铜 (Cu) 的酶，由血管平滑肌细胞/成纤维细胞分泌，随后与内皮细胞表面结合，清除细胞外 O ₂ ^-并保留内皮功能。 SOD3 活性依赖于铜，由铜转运蛋白 ATP7A 提供，但 Cav-1 是否调节 ATP7A-SOD3 轴及其在氧化应激介导的血管功能障碍中的作用尚未研究。在这里，我们发现 Cav-1 ^-/-血管中 SOD3 的活性显着降低，但 SOD1 的活性没有显着降低，通过重新表达 Cav-1 或补充 Cu 可以挽救这种活性。 Cav-1 的缺失会减少 ATP7A 蛋白，但不会减少 mRNA，这是由 ATP7A 泛素化和蛋白酶体降解介导的。 ATP7A 与 Cav-1 结合，并与 SOD3 共定位于血管组织或细胞的小窝/脂筏或核周中。 Cav-1 ^-/-小鼠中内皮依赖性血管舒张功能受损可通过 SOD3 基因转移或 ATP7A 过表达转基因小鼠来挽救。 这些数据揭示了 Cav-1 通过防止 ATP7A 泛素化和蛋白酶体降解来稳定 ATP7A 蛋白表达，从而增加 SOD3 活性，从而防止血管氧化应激介导的内皮功能障碍。