Spinster homolog 2 (SPNS2) deficiency drives endothelial cell senescence and vascular aging via promoting pyruvate metabolism mediated mitochondrial dysfunction.

Abstract

Endothelial cell (EC) senescence and vascular aging are important hallmarks of chronic metabolic diseases. An improved understanding of the precise regulation of EC senescence may provide novel therapeutic strategies for EC and vascular aging-related diseases. This study examined the potential functions of Spinster homolog 2 (SPNS2) in EC senescence and vascular aging. We discovered that the expression of SPNS2 was significantly lower in older adults, aged mice, hydrogen peroxide-induced EC senescence models and EC replicative senescence model, and was correlated with the expression of aging-related factors. in vivo experiments showed that the EC-specific knockout of SPNS2 markedly aggravated vascular aging by substantially, impairing vascular structure and function, as evidenced by the abnormal expression of aging factors, increased inflammation, reduced blood flow, pathological vessel dilation, and elevated collagen levels in a naturally aging mouse model. Moreover, RNA sequencing and molecular biology analyses revealed that the loss of SPNS2 in ECs increased cellular senescence biomarkers, aggravated the senescence-associated secretory phenotype (SASP), and inhibited cell proliferation. Mechanistically, silencing SPNS2 disrupts pyruvate metabolism homeostasis via pyruvate kinase M (PKM), resulting in mitochondrial dysfunction and EC senescence. Overall, SPNS2 expression and its functions in the mitochondria are crucial regulators of EC senescence and vascular aging.