Testosterone promote myocardial hypertrophy in postmenopausal hypertensive women by regulating the plasma membrane transition of the cardiomyocytes

Objectives The estrogen level of postmenopausal women decreased sharply, while the androgen level did not decrease significantly, which was characterized by the inversion of estrogen / androgen ratio. Therefore, it could be observed that relative excess androgen in the circulation of postmenopausal women, which may be one of the reasons for the increase of cardiovascular disease in postmenopausal women. In this study, the specific mechanisms of testosterone-induced myocardial hypertrophy in ovariectomized SHR was explored. Methods 30 SHR were randomly divided into five groups: Sham group (n=6), OVX group (n=6) , OVX+T group (n=6) , OVX+T+JR-AB2 group(n=6) and SHR+JR-AB2 group(n=6). Six WKY rats were employed as the negative control. The blood pressure, heart rate and echocardiography were recorded. Western Blot was used to detect the protein expression of mTORC2, Rictor, Atg9a, Anxa2. Moreover, the expression of autophagy-related proteins LC3 was observed. Results 1. The effects of testosterone on blood pressure and the structure of heart. Testosterone significantly increases SBP and DBP in ovariectomized SHR rats, with no effect on heart rate. The OVX+T group shows higher LVPWd, IVSd, and LVEF in M-mode echocardiography compared to controls. JR-AB improves LVPWd and IVSd but does not affect LVEF or heart rate. 2. The expression of protein changes induced by testosterone. Testosterone increases the expression of ANP, β-MHC, mTORC2, and Rictor in the OVX+T group. It also enhances autophagy, evidenced by increased LC3II and decreased P62 expression. JR-AB reduces the expression of ANP, β-MHC, mTORC2, Rictor, LC3II, and Atg9a in hypertrophic cardiomyocytes induced by testosterone. 3. The expression and translocation of Atg9a in cardiomyocytes. In normal cells, Atg9a is localized in the trans-Golgi network and colocalizes with TGN46. Testosterone treatment reduces the colocalization of Atg9a with TGN46 and increases Atg9a expression in cardiomyocytes. JR-AB promotes the colocalization of Atg9a with TGN46 and reduces Atg9a expression. Conclusions In ovariectomized SHR rats, testosterone induces cardiac hypertrophy by activating the mTORC2/Atg9a pathway, which facilitates the translocation of Atg9a within cardiomyocytes, while JR-AB improves testosterone-induced myocardial hypertrophy by specifically inhibiting the mTORC2 signaling pathway and mitophagy.