17β-Estradiol alleviates cardiac aging induced by d-galactose by downregulating the methylation of autophagy-related genes

Abstract

Intrinsic cardiac aging increases cardiovascular mortality and morbidity in the elderly. Estrogen helps reduce the risk of cardiovascular disease in women, with 17β-estradiol (17β-E2) activating the autophagy pathway and inhibiting vascular aging, mainly through estrogen receptor alpha (ER α) to prevent atherosclerosis. Abnormal methylation of autophagy-related genes can impact autophagic regulation. We hypothesized that 17β-E2, specifically 17β-E2 α, downregulates the methylation of autophagy factors and delays cardiac aging. Here, we used d-galactose, 17β-E2, and ER α receptor antagonist methyl-piperidino-pyrazole (MPP) to establish different aging models in mice divided into four groups, namely negative control, D.gal, D.gal + 17β-E2, and D.gal + 17β-E2 + MPP groups. Echocardiography showed that compared with the D.gal group group, the D.gal + 17β-E2 showed substantially increased cardiac function. The level of cardiac aging markers in mice in the D.gal + 17β-E2 group was lower than that in mice in the D.gal group. Beclin1, LC3, and Atg5 mRNA and protein expression levels in mice in the D.gal + 17β-E2 group were significantly increased compared with those in the D.gal group. Additionally, Beclin1, LC3, and Atg5 methylation levels were significantly decreased in the D.gal + 17β-E2 group. All the above values of the D.gal + 17β-E2 + MPP group were between those of the D.gal and D.gal + 17β-E2 groups. The expression of Dnmt1, Dnmt2, and Dnmt3A genes was the highest in the D.gal group. In summary, our results suggest that 17β-E2, specifically 17β-E2 α, promotes autophagy by downregulating the methylation of autophagy factors, thereby inhibiting galactose-induced cardiac aging in mice. 17β-E2 may be a potential therapeutic target to mitigate the effects of cardiac aging.