17β-Estradiol inhibits hydrogen peroxide-induced senescence and apoptosis in human umbilical vein endothelial cells by regulating the THBS1/TGF-β/Smad axis.

Before menopause, females exhibit a lower incidence of cardiovascular disease than age-matched males, possibly owing to the protective effects of sex hormones. 17β-estradiol (17β-E2) protects against oxidative stress-induced injury by suppressing thrombospondin-1 (THBS1) expression in endothelial cells. Here, we examined the role of 17β-E2-mediated THBS1 suppression in preventing cell senescence and apoptosis. Human umbilical vein endothelial cells (HUVECs) were cultivated and treated with siRNA or overexpression plasmids to regulate THBS1. HO, estrogen-activity modulating drugs, and LY2109761 (a TGF-β kinase inhibitor) treatments were applied. THBS1 knockdown repressed, and its overexpression aggravated, HO-induced cell injury, affecting cell death, proliferation, senescence, and apoptosis. 17β-E2 inhibited THBS1 mRNA and protein expression time- and dose-dependently, by targeting ERβ. THBS1 overexpression blocked 17β-E2 from preventing HO-induced injury, significantly activating the TGF-β/Smad pathway. 17β-E2 inhibited HO-induced oxidative stress by downregulating THBS1 expression and TGF-β/Smad signaling in HUVECs. The THBS1/TGF-β/Smad axis could thus be a therapeutic target.