Abstract 4129520: The mechanism of cardiac hypertrophy induced by testosterone in postmenopausal women through the activation of the mTORC2/Atg9a

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 model of postmenopausal hypertension was established by bilateral ovariectomy in spontaneously hypertensive rats (SHR), and the specific mechanism of testosterone-induced myocardial hypertrophy in ovariectomized SHR was explored. Methods: 24 SHR were randomly divided into four groups: WKY group (n=6), sham operation group (Sham group, n=6), bilateral ovariectomized group (OVX group, n=6) and testosterone propionate intervention group (OVX+T group, 6mg/kg/Weekly, im for 4 weeks, n=6). Western Blot was used to detect the protein expression of β-MHC, ANP, Androgen receptor, Akt, p-Akt, mTORC2 and its subunits Rictor. Moreover, the expression of autophagy-related proteins LC3 was observed. Results: 1. The study revealed that the expression of β-MHC and ANP was significantly increased in both the OVX and OVX+T groups when compared to the WKY and Sham groups. Remarkably, testosterone induced a more significant cardiac hypertrophy response than observed in the OVX group alone. Additionally, the expression of androgen receptors was markedly upregulated in both the OVX and OVX+T groups. These findings strongly suggest that testosterone primarily induces myocardial hypertrophy in SHR after ovariectomy through androgen receptors. 2. Although no significant difference in mTORC2 expression was noted between the WKY, Sham, and OVX groups, testosterone exhibited a notable capacity to activate mTORC2 expression and the p-Rictor subunit in the OVX+T group. 3. The expression of LC3II/LC3I and mitochondrial fission protein DRP1 were increased in the OVX+T group when compared to the WKY, Sham, and OVX groups. While the expression of MFN2 in the four groups shows no significant difference. Meanwhile, the expression of Atg9a was increased in OVX+T group. The results indicate that testosterone might activate mitophagy via inducing the expression of Atg9a. Conclusions: In bilateral ovariectomized SHR, testosterone has the potential to activate mitophagy by activating the mTORC2/Atg9a pathway, which, in turn, leads to cardiac hypertrophy.