Crosstalk Between Mitochondrial Hyperacetylation and Oxidative Stress in Vascular Dysfunction and Hypertension

Significance: 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. Recent Advances: 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. Critical Issues: 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. Future Directions: 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.