Hypertension-induced vascular remodeling is a major contributor to cardiovascular morbidity and is characterized by endothelial dysfunction, vascular smooth muscle cell phenotypic switching, fibrosis, and inflammation. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase, plays an important role in maintaining mitochondrial homeostasis, regulating redox balance, and modulating cellular energy metabolism. Emerging evidence suggests that SIRT3 deficiency accelerates hypertensive vascular remodeling through multiple mechanisms. In vascular smooth muscle cells (VSMCs), reduced SIRT3 activity enhances mitochondrial reactive oxygen species generation, promotes glycolytic reprogramming, and contributes to phenotypic switching and proliferation. In endothelial cells, SIRT3 mitigates oxidative stress (OS) by regulating the activity of superoxide dismutase 2, thereby preserving nitric oxide (NO) bioavailability and improving vascular function. SIRT3 also suppresses fibroblast-to-myofibroblast transformation by inhibiting the transforming growth factor-β/Smad3 pathway, thereby reducing vascular fibrosis. Furthermore, SIRT3 regulates macrophage metabolic reprogramming and autophagy, inhibits NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation, and attenuates vascular inflammation. In perivascular adipose tissue, SIRT3 deficiency exacerbates angiotensin II-induced fibrosis and cytokine secretion, thereby aggravating vascular dysfunction. Collectively, SIRT3 acts as a mitochondrial regulator against hypertension-induced oxidative and inflammatory injury. Targeting SIRT3-dependent pathways may represent a promising therapeutic approach to restore vascular homeostasis and prevent hypertensive vascular remodeling.
