Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
Antioxid Redox Signal. 2019 Oct 1;31(10):710-721. doi: 10.1089/ars.2018.7632. Epub 2019 Feb 28.
Vascular dysfunction plays a key role in the development of arteriosclerosis, heart disease, and hypertension, which causes one-third of deaths worldwide. Vascular oxidative stress and metabolic disorders contribute to vascular dysfunction, leading to impaired vasorelaxation, vascular hypertrophy, fibrosis, and aortic stiffening. Mitochondria are critical in the regulation of metabolic and antioxidant functions; therefore, mitochondria-targeted treatments could be beneficial. Vascular dysfunction is crucial in hypertension pathophysiology and exhibits bidirectional relationship. Metabolic disorders and oxidative stress contribute to the pathogenesis of vascular dysfunction and hypertension, which are associated with mitochondrial impairment and hyperacetylation. Mitochondrial deacetylase Sirtuin 3 (Sirt3) is critical in the regulation of metabolic and antioxidant functions. Clinical studies show that cardiovascular disease risk factors reduce Sirt3 level and Sirt3 declines with age, paralleling the increased incidence of cardiovascular disease and hypertension. An imbalance between mitochondrial acetylation and reduced Sirt3 activity contributes to mitochondrial dysfunction and oxidative stress. We propose that mitochondrial hyperacetylation drives a vicious cycle between metabolic disorders and mitochondrial oxidative stress, promoting vascular dysfunction and hypertension. The mechanisms of mitochondrial dysfunction are still obscure in human hypertension. Mitochondrial hyperacetylation and oxidative stress contribute to mitochondrial dysfunction; however, regulation of mitochondrial acetylation, the role of GCN5L1 (acetyl-CoA-binding protein promoting acetyltransferase protein acetylation) acetyltransferase, Sirt3 deacetylase, and acetylation of specific proteins require further investigations. There is an urgent need to define molecular mechanisms and the pathophysiological role of mitochondrial hyperacetylation, identify novel pharmacological targets, and develop therapeutic approaches to reduce this phenomenon.
血管功能障碍在动脉硬化、心脏病和高血压的发展中起着关键作用，这些疾病导致了全球三分之一的死亡。血管氧化应激和代谢紊乱导致血管功能障碍，导致血管舒张功能受损、血管肥大、纤维化和主动脉僵硬。线粒体在代谢和抗氧化功能的调节中至关重要；因此，针对线粒体的治疗可能是有益的。
血管功能障碍在高血压病理生理学中起着关键作用，并表现出双向关系。代谢紊乱和氧化应激导致血管功能障碍和高血压的发病机制，与线粒体损伤和乙酰化过度有关。线粒体去乙酰化酶 Sirtuin 3（Sirt3）在代谢和抗氧化功能的调节中起着关键作用。临床研究表明，心血管疾病的危险因素会降低 Sirt3 的水平，并且随着年龄的增长，Sirt3 水平下降，与心血管疾病和高血压的发病率增加相平行。线粒体乙酰化和 Sirt3 活性降低之间的不平衡导致线粒体功能障碍和氧化应激。我们提出，线粒体过度乙酰化导致代谢紊乱和线粒体氧化应激之间的恶性循环，促进了血管功能障碍和高血压的发生。
线粒体功能障碍的机制在人类高血压中仍不清楚。线粒体过度乙酰化和氧化应激导致线粒体功能障碍；然而，线粒体乙酰化的调节、GCN5L1（促进乙酰转移酶蛋白乙酰化的乙酰辅酶 A 结合蛋白）乙酰转移酶的作用、Sirt3 去乙酰化酶以及特定蛋白质的乙酰化，需要进一步研究。
迫切需要定义线粒体过度乙酰化的分子机制和病理生理学作用，确定新的药理学靶点，并开发减少这种现象的治疗方法。
