SIRT3 inhibition promotes age-associated vascular impairment by mediating mitochondrial dysfunction and endothelial-to-mesenchymal transition.

BACKGROUND

Vascular aging profoundly impacts on cardiovascular disease. Sirtuin 3 (SIRT3) is a key regulator of metabolic homeostasis whose expression declines with age; however, the mechanisms linking SIRT3 deficiency to age-associated vascular impairment remain unclear. Here, we investigated whether SIRT3 deficiency drives age-associated vascular impairment by inducing mitochondrial dysfunction and initiating endothelial-to-mesenchymal transition (EndMT).

METHODS

Vascular morphology, aging-related protein expression, and endothelium-dependent vasorelaxation were evaluated in young (5-month-old) and aged (21-month-old) wild-type mice, alongside Sirt3 knockout (KO) mice. EndMT was assessed using immunofluorescence and immunoblotting. Mitochondrial function was examined by assessing mitochondrial morphology, determining the protein expression of mitochondrial biogenesis-related factors and superoxide dismutase 2, and measuring mitochondrial reactive oxygen species levels. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with SIRT3-targeting siRNA and treated with H2O2 to induce premature senescence, after which mitochondrial function and EndMT marker levels were analyzed.

RESULTS

Vascular aging was characterized by increased expression of aging-related proteins, endothelial dysfunction, and medial calcification and fibrosis, which were linked to EndMT and mitochondrial dysfunction in aged endothelial cells (ECs). SIRT3 expression was downregulated in aging vascular ECs. Sirt3 KO mice exhibited exacerbated vascular calcification and fibrosis, associated with the promotion of aging-induced EndMT and the aggravation of mitochondrial dysfunction. Silencing SIRT3 in prematurely senescent HUVECs confirmed its role in driving EndMT and mitochondrial dysfunction.

CONCLUSIONS

SIRT3 deficiency promotes age-related vascular impairment potentially by mediating EndMT and mitochondrial dysfunction, Thus, SIRT3 represents a potential therapeutic target for delaying vascular aging and associated cardiovascular diseases.