Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200081, China.
Department of Thyroid Breast and Vascular Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, 1279 Sanmen Road, Hongkou District, Shanghai, 200081, China.
Cardiovasc Drugs Ther. 2024 Oct;38(5):885-893. doi: 10.1007/s10557-023-07477-6. Epub 2023 Jun 8.
To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein.
Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway-related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated.
Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling.
Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.
迄今为止，针对内皮功能障碍的治疗方法主要集中在改善已确定的动脉粥样硬化（AS）危险因素上，而不是明确针对基于内皮的机制。本文深入探讨了内皮损伤的病理机制。
利用慢病毒使小鼠的血管内皮钙黏蛋白 1（Cav1）敲低，并使用高脂肪饮食诱导 AS。检测小鼠体重、血糖、胰岛素、血脂参数、主动脉斑块、内皮损伤、血管型一氧化氮合酶（eNOS）、损伤标志物和氧化应激。研究 Cav1 敲低对 PKCzeta 含量和 PI3K/Akt/eNOS 通路相关蛋白水平的影响，以及 PKCzeta 与 Akt 的结合。体外利用 PKCzeta 抑制剂 ZIP 处理 HUVECs，评估 ZIP 对细胞活力、炎症反应、氧化应激和 Akt 激活的影响。
在 8 周的时间内，Cav1 敲低对小鼠的体重或血糖没有显著影响，但显著降低了胰岛素、血脂参数、内皮损伤、E-选择素和氧化应激水平，同时升高了 eNOS 水平。此外，Cav1 敲低触发了 PKCzeta 富集和 PI3K/Akt/eNOS 通路的激活减少。PKCzeta 在没有与 Cav1 偶联的情况下对细胞有积极影响，并且在 Cav1/PKCzeta 偶联后，ZIP 对 PKCzeta-Akt 结合没有明显影响。
Cav1/PKCzeta 偶联拮抗了 PI3K 对 Akt 的激活，导致 eNOS 功能障碍、胰岛素抵抗和内皮细胞损伤。
