SIRT3 suppresses vascular endothelial senescence via DHRS2 and contributes to the anti-vascular aging effect of Bazi Bushen capsule

AIMS: Vascular and endothelial aging are significant causes of chronic diseases among the elderly. This study investigated the specific mechanism by which sirtuin 3 (SIRT3) regulates vascular endothelial senescence and the beneficial role of Bazi Bushen capsule (BZBS) in preventing vascular aging. METHODS: Human umbilical vein endothelial cells and mouse aortic endothelial cells were cultured with D-galactose (D-gal) to induce aging and evaluate the beneficial effects of the SIRT3-dehydrogenase/reductase member 2 (DHRS2) axis on the inhibition of vascular endothelial aging. d-Gal was injected intraperitoneally into wild-type and Sirt3 knockout mice, while BZBS was administered orally. Histochemical staining, immunohistochemistry, and western blotting assays were used to explore the beneficial effects of BZBS against aging-associated vascular remodelling. Endothelial cell function assays were used to evaluate the role of BZBS in suppressing endothelial aging in vitro. RESULTS: SIRT3 deacetylated DHRS2 and modulated the translation of DHRS2. The SIRT3-DHRS2 axis played an important role in preserving mitochondrial homeostasis and reducing reactive oxygen species generation through suppressing endothelial nitric oxide synthase (eNOS) translocating to mitochondria and eNOS-Thr495 phosphorylation mediated by protein kinase C δ (PKCδ). BZBS mitigated vascular remodelling and relieved endothelial oxidative stress via the SIRT3-DHRS2 axis. CONCLUSION: SIRT3 activates DHRS2-PKCδ to stop aging in endothelial cells by inhibiting uncoupled eNOS translocating to mitochondria. BZBS rescued vascular aging and endothelial dysfunction via the SIRT3-DHRS2 axis. Revealing a protective mechanism by which SIRT3 inhibits endothelial senescence, this study provides evidence for BZBS in delaying vascular aging.