PS-B02-10: MTOR INHIBITOR IMPROVES TESTOSTERONE-INDUCED MYOCARDIAL HYPERTROPHY IN HYPERTENSIVE RATS

Abstract

Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy in postmenopausal women is significantly increased worldwide. Our team previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized spontaneously hypertensive rats aged 12 weeks were used to study the effects of testosterone T 2.85 mg/kg/weekly im on blood pressure and myocardial tissue. On the basis of antihypertensive therapy chlorthalidone 8 mg/kg/day ig, the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin 0.8 mg/kg/day Vs 1.5 mg/kg/day Vs 2 mg/kg/day ip in OVX+ estrogens E 9.6 mg/Kg/day, ig+T group was further evaluated. After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length, cross-sectional area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor mTOR, ribosomal protein S6 kinase S6K1, 4E-bindiong protein 1 4EBP1 and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive women with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.