Peroxisome Proliferator-activated Receptor , Coactivator 1 Deletion Induces Angiotensin II-Associated Vascular Dysfunction by Increasing Mitochondrial Oxidative Stress and Vascular Inflammation
Peroxisome Proliferator-activated Receptor , Coactivator 1 Deletion Induces Angiotensin II-Associated Vascular Dysfunction by Increasing Mitochondrial Oxidative Stress and Vascular Inflammation
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DOI：
10.1161/atvbaha.113.301717
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发表时间：
2013-08-01
影响因子：
8.7
通讯作者：
Schulz, Eberhard
中科院分区：
文献类型：
--
作者：
Kroeller-Schoen, Swenja;Jansen, Thomas;Schulz, Eberhard
过氧化物酶体增殖物激活受体辅激活因子1（Peroxisome proliferator-activated receptor，coactivator 1，PGC-1）是线粒体生物发生和功能的重要调节因子。由于功能障碍的线粒体可能参与血管疾病的发病机制，目前的研究旨在探讨体内PGC-1缺乏在慢性血管紧张素II（ATII）治疗过程中的影响。（0.1 mg/kg/天，持续7天）未引起野生型小鼠的血管功能障碍，它导致PGC-1敲除小鼠内皮依赖性和内皮非依赖性舒张功能受损。与此同时，ATII处理的PGC-1基因敲除小鼠的主动脉环中氧化应激增加，而一氧化氮的产生没有观察到变化。通过使用线粒体特异性超氧化物染料MitoSox和复合物I抑制剂鱼藤酮，我们确定了线粒体呼吸链作为体内主要的PGC-1依赖性活性氧来源，伴随着血管炎症和细胞衰老的增加。在体内治疗与靶向的抗氧化剂Mito-TEMPO部分纠正内皮功能障碍，防止血管炎症ATII治疗的PGC-1小鼠，这表明线粒体活性氧在这种setting.ConclusionsPGC-1删除诱导血管功能障碍和炎症慢性ATII输液通过增加线粒体活性氧的生产。
ObjectivePeroxisome proliferator-activated receptor , coactivator 1 (PGC-1) is an important mediator of mitochondrial biogenesis and function. Because dysfunctional mitochondria might be involved in the pathogenesis of vascular disease, the current study was designed to investigate the effects of in vivo PGC-1 deficiency during chronic angiotensin II (ATII) treatment.Approach and ResultsAlthough ATII infusion at subpressor doses (0.1 mg/kg per day for 7 days) did not cause vascular dysfunction in wild-type mice, it led to impaired endothelial-dependent and endothelial-independent relaxation in PGC-1 knockout mice. In parallel, oxidative stress was increased in aortic rings from ATII-treated PGC-1 knockout mice, whereas no change in nitric oxide production was observed. By using the mitochondrial-specific superoxide dye MitoSox and complex I inhibitor rotenone, we identified the mitochondrial respiratory chain as the major PGC-1-dependent reactive oxygen species source in vivo, accompanied by increased vascular inflammation and cell senescence. In vivo treatment with the mitochondria-targeted antioxidant Mito-TEMPO partially corrected endothelial dysfunction and prevented vascular inflammation in ATII-treated PGC-1 mice, suggesting a causative role of mitochondrial reactive oxygen species in this setting.ConclusionsPGC-1 deletion induces vascular dysfunction and inflammation during chronic ATII infusion by increasing mitochondrial reactive oxygen species production.