Testosterone protects cardiomyocytes against hydrogen peroxide-induced aging by upregulating IGF1 and SIRT1 pathways

Objective: To investigate the role of IGF1 and SIRT1 pathways in protection of hydrogen peroxide (H2O2)-induced aging in H9c2 rat cardiomyocyte cells by testosterone. Methods: The cells were treated with testosterone or up- or down-regulated for the IGF1 and SIRT1 genes and assessed for apoptosis, aging and expression of relevant genes. Results: Aging was induced and the expression of SIRT1 and IGF1 was down-regulated after H2O2 treatment in H9c2 cells. The aging was attenuated in a dose-dependent manner after the cells were exposed to testosterone. Down-regulation of SIRT1 and IGF1expression was offset in the H2O2-treated cells co-treated with testosterone. Up- or down-regulation of IGF1 significantly reduced or increased senescence-associated beta-galactosidase (SA-beta-gal) cells and the ROS level, respectively. In addition, SIRT1 expression was regulated by IGF1 expression. Down- or up-regulation of SIRT1 significantly decreased or increased the IGF1 levels, respectively. Furthermore, after IGF1 and SIRT1 knockdown, testosterone did not protect the cells from senescence. Testosterone, and overexpression of IGF1 and SIRT1 also up-regulated the expression of the fetal genes SERCA2 and MYH6 and down-regulated the expression of the ACTA1 and MYH7 genes. Conclusions: Our data indicate that testosterone can attenuate cardiomyocyte aging induced by H2O2 and up-regulate SIRT1 and IGF1. The IGF1and SIRT1 pathway may be new targets to treat heart aging and heart failure.