Peroxisome Proliferator-Activated Receptor α Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Angiotensin II-Induced ROS Production.
Peroxisome Proliferator-Activated Receptor α Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Angiotensin II-Induced ROS Production.
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过氧化物酶体增殖物激活受体 α 通过保护血管平滑肌细胞免受血管紧张素 II 诱导的 ROS 产生来减轻高血压血管重塑
DOI：
10.3390/antiox11122378
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发表时间：
2022-11-30
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影响因子：
--
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血管重构是高血压病发生发展的基础，其中血管平滑肌细胞（VSMC）功能障碍起着至关重要的作用。既往研究表明，贝特类药物激活过氧化物酶体增殖物激活受体α（PPARα）具有独立于降脂作用的心血管获益。然而，其内在机制仍然不完全清楚。本研究采用VSMC特异性Ppa缺陷小鼠，探讨了PPARα在血管紧张素II（Ang II）诱导的血管重构和高血压中的作用。Ang Ⅱ处理后，VSMCs的PPARα表达明显下调。VSMC中的PPARα缺陷显著加重Ang II诱导的高血压和血管僵硬度，而对心功能影响不大。形态学分析表明，VSMC特异性Ppara缺陷小鼠表现出加重的血管重塑和氧化应激。在体外实验中，在Ang II处理的原代VSMCs中，PPARα缺乏显著增加了线粒体活性氧化物质（ROS）的产生。最后，Wy14643通过激活PPARα，以依赖于PPARα的方式改善Ang II诱导的ROS生成和血管重构。综上所述，这些数据表明，PPARα通过减少VSMCs中ROS的产生在Ang II诱导的高血压中发挥关键的保护作用，从而为高血压疾病提供了潜在的治疗靶点。
Vascular remodeling is the fundamental basis for hypertensive disease, in which vascular smooth muscle cell (VSMC) dysfunction plays an essential role. Previous studies suggest that the activation of peroxisome proliferator-activated receptor α (PPARα) by fibrate drugs has cardiovascular benefits independent of the lipid-lowering effects. However, the underlying mechanism remains incompletely understood. This study explored the role of PPARα in angiotensin II (Ang II)-induced vascular remodeling and hypertension using VSMC-specific Ppara-deficient mice. The PPARα expression was markedly downregulated in the VSMCs upon Ang II treatment. A PPARα deficiency in the VSMC significantly aggravated the Ang II-induced hypertension and vascular stiffness, with little influence on the cardiac function. The morphological analyses demonstrated that VSMC-specific Ppara-deficient mice exhibited an aggravated vascular remodeling and oxidative stress. In vitro, a PPARα deficiency dramatically increased the production of mitochondrial reactive oxidative species (ROS) in Ang II-treated primary VSMCs. Finally, the PPARα activation by Wy14643 improved the Ang II-induced ROS production and vascular remodeling in a VSMC PPARα-dependent manner. Taken together, these data suggest that PPARα plays a critical protective role in Ang II-induced hypertension via attenuating ROS production in VSMCs, thus providing a potential therapeutic target for hypertensive diseases.
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