Urolithin A alleviates vascular remodeling through mitochondrial SIRT3-mediated SOD2 deacetylation and antioxidation in hypertensive rats.

<h4>Objectives</h4>Urolithin A (UA) is a natural polyphenolic compound produced by gut bacteria. Vascular remodeling contributes to hypertension, and vascular smooth muscle cells (VSMCs) proliferation and migration are important processes in vascular remodeling.<h4>Methods</h4>VSMCs were obtained from the thoracic aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Intraperitoneal injections of UA (50 mg/kg, every 2 days for 4 weeks) were performed in SHR.<h4>Results</h4>UA attenuated proliferation and migration, reduced mitochondrial reactive oxygen species (mitoROS) levels, and increased SOD2 activity in VSMCs of SHR, which were prevented by SOD2 knockdown. UA promoted mitochondrial short-length SIRT3 (SL-SIRT3) production and SOD2 deacetylation. SIRT3 inhibitor 3-TYP abolished the effects of UA on SOD2 deacetylation, mitoROS levels and VSMCs proliferation and migration. Repeated intraperitoneal injection of UA every 2 days for 4 weeks attenuated vascular remodeling and hypertension, increased SL-SIRT3 levels and SOD2 activity, and reduced SOD2 acetylation and mitoROS levels in aorta and mesenteric arteries of SHR.<h4>Conclusion</h4>UA attenuates VSMCs proliferation and migration in SHR by increasing mitochondrial SL-SIRT3 level, and subsequent SOD2 deacetylation and mitoROS reduction in SHR. Long-term administration of UA attenuates vascular remodeling, hypertension and oxidative stress in SHR.