TESTOSTERONE INDUCES POSTMENOPAUSAL HYPERTENSIVE HYPERTROPHY THROUGH INHIBITING THE ACTIVATION OF AMPK- FOXO1/MURF1 SIGNALING PATHWAY

Abstract

Objective: It has been found that relative elevated level of testosterone could exacerbates postmenopausal hypertensive left ventricular hypertrophy(PM-HTN-LVH), but the mechanisms responsible are unknown. Moreover, MuRF1, a muscle-specific E3 ubiquitin ligase in the ubiquitination process, was newly identified as a negative regulatory factor of myocardial and muscle tissue in exerting a protective functions on the cardiomyocyte hypertrophy. There are little study to certify whether MuRF1 took part in testosterone-induced PM-HTN-LVH. Design and method: Femal spontaneously hypertensive rats (SHR) were ovariectomized (OVX group) or sham-operated (Sham group) at 12 weeks and then the OVX group were intramuscularly injected the testosterone (T 2.85 mg/kg/ quaque omni die im) (OVX+T group) or vehicle (OVX+ vehicle group) for 4 weeks. Futher, Cultured cardiomyocytes were respectively stimulated with different concentration gradients of testosterone for 24h, then measured the expression of myosin heavy chain (MHC) and MuRF1, as well as the phosphorylation levels of AMPK(p-AMPK) and Forkhead box O 1 (p-FOXO1), were separately measured using western blot. Results: After 4 weeks of testosterone supplementation, SHR heart exhibited significant increments in the heart weight/tibial length and the levels of IVST, LVPWT, LVM and the expression of MHC, and have a lower expression of the MuRF1, p-AMPK and p-FOXO1 in the OVX+T group, compared with OVX group and Sham group. Moreover, the expression level of p-AMPK and p-FOXO1 in the heart were at least twice as many as gastrocnemius muscle among the three group, but the MuRF1 was equivalent between heart and gastrocnemius muscle. In vivo, after the treatment of different gradients of testosterone for 24h, the protein expression of MHC showed an S-shaped growth trend and MuRF1, p-AMPK and p-FOXO1 presented with reverse S-shaped reduction along with increasing of testosterone concentration, peaking at 10-6M testosterone. Conclusions: The present study demonstrates that testosterone induces PM-HTN-LVH by modulating the atrophy related AMPK-FOXO1/MuRF1 signaling pathway in vitro and vivo. Increased the heart expression of MuRF1 by activation of AMPK may reverse testosterone-mediated PM-HTN-LVH, which might cause little change of MuRF1 expression in the skeletal muscle resulting in the muscle atrophy.