Wang Fu, Ma Hui, Liang Wen-Jing, Yang Jing-Jing, Wang Xue-Qing, Shan Mei-Rong, Chen Yuan, Jia Min, Yin Ya-Ling, Sun Xue-Ying, Zhang Jia-Ning, Peng Qi-Sheng, Chen Yu-Guo, Liu Li-Ying, Li Peng, Guo Tao, Wang Shuang-Xi
The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
Department of Rehabilitation Medicine, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, China.
Oncotarget. 2017 Feb 7;8(6):9021-9034. doi: 10.18632/oncotarget.14462.
Proteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated.
Lovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H2O2, TNFα, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues.
Upregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.
蛋白酶体相关的氧化应激被认为会导致内皮功能障碍，这是心血管疾病（CVD）的早期事件。他汀类药物作为HMG-CoA还原酶抑制剂，可预防CVD中的内皮功能障碍。然而，他汀类药物介导的内皮功能正常化的分子机制尚未完全阐明。
洛伐他汀在培养的人脐静脉内皮细胞（HUVECs）中呈时间/剂量依赖性增加miR-29b表达并降低蛋白酶体活性。抗miR-29b或PA200的过表达消除了洛伐他汀对HUVECs中蛋白酶体活性的诱导抑制作用。相反，pre-miR-29b或PA200 siRNA模拟了洛伐他汀对蛋白酶体活性的这些作用。洛伐他汀抑制了多种氧化剂诱导的氧化应激，包括氧化型低密度脂蛋白（ox-LDL）、过氧化氢（H2O2）、肿瘤坏死因子α（TNFα）、同型半胱氨酸硫内酯（HTL）和高糖（HG），在HUVECs中抑制miR-29b可逆转这些作用。体外分析表明，洛伐他汀使分离的大鼠主动脉在暴露于多种心血管危险因素时，乙酰胆碱诱导的内皮依赖性舒张和氧化还原状态正常化。体内分析显示，给予洛伐他汀可显著抑制高血糖、血脂异常和高同型半胱氨酸血症大鼠的氧化应激并预防内皮功能障碍，同时增加主动脉组织中miR-29b表达、降低PA200蛋白水平并抑制蛋白酶体活性。
miR-29b表达上调是多种心血管危险因素通过PA200依赖的蛋白酶体介导的氧化应激诱导内皮功能障碍的共同机制，而洛伐他汀可预防这一机制。
