Objective: To investigate whether relatively elevated testosterone after ovarian failure contributes to the development of postmenopausal hypertension and hypertension-associated left ventricular hypertrophy in women, and to elucidate the underlying mechanisms. Design and method: Here we performed bilateral ovariectomy for 12-week-old female spontaneously hypertensive rats (SHRs) to mimic postmenopausal condition (OVX group) then intramuscularly injected the testosterone (T 2.85 mg/kg/ quaque omni die im) (OVX+T group) for 4 weeks to investigate the effects of testosterone on blood pressure, cardiac function and structure in ovariectomized SHRs, and futher to certify AMPK-FOXO1-Murf1 signaling pathway states, identified for functioning through the ubiquitin-proteasome-mediated degradation of cardiac hypertrophic proteins. Results: We find that testosterone plays a deleterious role in ovariectomized SHRs with manifestations in the OVX+T group as follow. 1) Exposure to physiological level of serum testosterone could elevate the blood pressure level. Furthermore, it exacerbate left ventricular hypertrophy and fibrosis on the basis of using diuretic chlorthalidone anti-hypertensive treatment. 2)The expression of pro-hypertrophic and pro-fibrotic proteins were significantly increased but both of the AMPK and FOXO1 phosphorylation rates, the atrophy protein Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/Atrogin-1, poly-ubiquitinated proteins, catalytic (20SPT), regulatory subunits (19SPT) of the constitutive proteasome and ATP-dependent chymotrypsin-like activity(ChT-L) were most significantly decreased in the left ventricular heart tissue in the OVX+T group. 3)AMPK activation by pharmacological activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) had strong positive correlations with myocyte area, FOXO1 phosphorylation rates and atrophy protein of H9C2 cell line in vitro. 4)AICAR could lower blood pressure and reverse left ventricular hypertrophy and fibrosis alongwith re-establishment expression of the afore-mentioned atrophy proteins, constitutive proteasome proteins and poly-ubiquitinated proteins, FOXO1 phosphorylation rates and normalized ChT-L activity in the OVX+T+LST group, moreover, these show a positive dose-dependent relationship. Conclusions: Testosterone facilitates hypertension and left ventricular hypertrophy in ovariectomized SHRs, likely by inhibiting AMPK–FOXO1 signaling and downstream ubiquitin–proteasome–mediated proteolysis; AICAR lowers blood pressure and reverses hypertrophy, highlighting AMPK activation as a potential therapy for postmenopausal hypertension and target-organ damage.
Zhu et al. (Fri,) studied this question.