mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats

Abstract

Compelling evidence have described 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 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 im) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8mg/kg/day Vs 1.5mg/kg/day Vs 2mg/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 (TL), area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, β- 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 female rats with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy

Physiological Impact of a Synthetic Elastic Protein in Arterial Diseases Related to Alterations of Elastic Fibers: Effect on the Aorta of Elastin-Haploinsufficient Male and Female Mice

“…However, SEP increased the inner and outer diameters of the ascending aorta in Eln +/+ mice only and mildly elevated the total heart and left ventricle weights of males, not females, compared to controls and/or females, independently of the genotype. The sex-dependent effect of SEP on heart weight is consistent with previous results, showing that (i) cardiac hypertrophy is favored by the male hormone testosterone and inhibited by the female hormone estrogens [ 39 ] and that (ii) the injected elastin peptide binding to the ERC improves the heart rate–blood pressure product (= heart work) in male rats, in a NO-dependent manner (proven post-ischemia) [ 40 ], which correlates with the left ventricle mass [ 41 ]. The moderate elevation of the heart weight observed after SEP treatment resembles the cardiac hypertrophy induced by the elastin production stimulator minoxidil in male rats and mice [ 26 , 27 , 28 ].…”

“…Such sex-related differences in response to SEP treatment are not surprising since, as indicated above, sex hormones have been shown to interfere with several pathophysiological mechanisms, such as cardiac hypertrophy, which is favored by the male hormone testosterone and inhibited by the female hormone estrogens [ 39 ]. A differential structural and functional impact of pharmacological treatment with minoxidil (an elastin production inducer) on arteries has also been demonstrated as a function of sex.…”

Association between Excessive Dietary Branched-Chain Amino Acids Intake and Hypertension Risk in Chinese Population

“…Atherosclerotic lesions of vascular smooth muscle cells (VSMCs) are also associated with activated mTOR [45]. Chen et al reported that in hypertensive rats, cardiac hypertrophy, elevated BP, as well as higher levels of mTOR were observed, while by giving an mTOR inhibitor, the BP was decreased [46]. Therefore, as we thought, BCAAs perhaps could directly result in elevated blood pressure by activating the Akt/mTORC1 signal pathway.…”

Sex Differences in Lipid Metabolism: Implications for Systemic Lupus Erythematosus and Cardiovascular Disease Risk

“…With this respect, increased mTORC1 activity has been observed in the liver and heart tissue of young female mice compared to male mice of the same age ( 92 ), and rapamycin treatment in mice also has sex specific effects on mTORC1 and mTORC2 ( 93 ). mTOR inhibition has also been shown to improve testosterone-induced myocardial hypertrophy in hypertensive rats ( 94 ), together supporting the potential sex-specific effects of mTOR on cardiovascular health. This suggests an alternative metabolic pathway to liver-x-receptors that oestradiol may exert its cardioprotective effects in healthy women and could be disrupted in SLE ( Figure 3 ).…”