Abstract
Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s 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 mammalian rapamycin receptor (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 (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) 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 i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, β-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-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 female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.
Highlights
Hypertension has been recognized as the most blatantly visible risk factor for cardiovascular and cerebrovascular diseases (Wang et al 2020, Zhang et al.2020)
The main finding of this study is that T, at physiologically relevant concentrations, leads to the development of female spontaneously hypertensive rats (SHR) left ventricular hypertrophy (LVH) after ovariectomy with associated increase in (1) left ventricle: cardiomyocyte area and LVMI, Heart weight (HW)/tibial length (TL); (2) left ventricular myocardial tissue mTORC1, S6K1,4EBP1, ANP,β-MHC and MMP-1 expression; (3) rat caudal artery systolic blood pressure (SBP) and diastolic blood pressure (DBP)
A major finding in our study is that T-mediated changes in the expression level of myocardial Mammalian rapamycin receptor (mTOR)/S6K1/4EBP1/eIF4E signaling pathway play a critical role in the pathogenesis and development of cardiac hypertrophy in SHR after ovariectomy
Summary
Hypertension has been recognized as the most blatantly visible risk factor for cardiovascular and cerebrovascular diseases (Wang et al 2020, Zhang et al.2020). It is known that left ventricular hypertrophy (LVH) is one of the most important manifestations of hypertension-mediated organ damage (HMOD) (Yildiz et al.2020, Cao et al 2019). In recent years, compelling evidences have demonstrated that the prevalence of hypertension and LVH in postmenopausal women have increased significantly worldwide (Luczak et al.2009, Brahmbhatt et al.2019). There is no doubt that antihypertensive treatment brings benefits to patients with hypertension and LVH (Dahlöf et al.2002). The current treatment of hypertension and HMOD has achieved certain results, LVH cannot be reversed to a greater extent even under the premise of reaching the standard for lowering blood pressure. New scientific understanding of the pathogenesis and treatment of postmenopausal hypertensive women and LVH needs to be investigated
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