Author + information
The pressure overload induced cardiac hypertrophy is a key risk factor for heart failure. However, the mechanism involved remains largely unknown. We previously showed that overexpression of valosin-containing protein (VCP) promotes cardiomyocytes survival in vitro. Here we tested the hypothesis that VCP protects heart against pressure overload-induced heart failure via promoting pro-survival signaling in cardiomyocyte in vivo.
Samples of human failing hearts were collected from the left ventricles of dilated cardiomyopathy patients undergoing heart transplants. Control samples were obtained from the left ventricles of normal heart donors of traffic accident victims. VCP transgenic (TG) mice and their wild-type littermates were subjected to sham or TAC surgery for 5 weeks. Echocardiography and invasive hemodynamic measurement were performed to evaluate the heart morphology and function. Histological analysis was used to measure the myocardial cross sectional area, fibrosis and apoptosis. The cardio Neonatal (1-2 day old) Sprague-Dawley rats were sacrificed and used for the isolation and cultures of neonatal rat cardiomyocytes (NRCMs). NRCMs were treated by Angiotensin II. The expression of mRNA and protein expression was evaluated by real time PCR and western blot, respectively.
VCP expression were found to be notably decreased in left ventricle (LV) tissues of dilated cardiomyopathy patients compared to healthy donor at both the mRNA and protein levels. A transgenic mouse (TG) with a cardiac specific overexpression of VCP was generated and compared to its litter-matched wild-type (WT). Pressure overload was induced by transverse aortic constriction (TAC) in mice for 5 weeks and sham control was included. Cardiac structure and function were measured by echocardiography and hemodynamic analysis. After 5 week TAC, compared to sham control, WT mice developed a dilated cardiac hypertrophy and cardiac dysfunction, reflected by a significant increase in LV chamber diameter, wall thickness and the ratio of LV weight/ tibia length, and a decrease in ejection fraction (71% vs 51%) as well as an increase in ratio of lung weight /tibia length, a marker of heart failure (all, P<0.01 vs WT sham). However, these pressure overload induced cardiac remodeling and dysfunction were significant suppressed in VCP TG TAC mice (P<0.05 vs WT TAC). Mechanistically, compared to sham control, VCP expression in LV tissues was found to be significant decreased in WT TAC mice, but not in VCP TG mice. VCP TG TAC mice showed a significant decrease in apoptosis of cardiomyocytes vs WT TAC mice (p<0.05). In addition, overexpression of VCP increased the phosphorylation of AKt at 473 and the expression of protein kinase C α in VCP TG mouse heart in vivo and in isolated cardiomyocytes in vitro which was abolished by the deletion of Rictor, indicating an activation of mammalian target of rapamycin complex 2 (mTORC2) in cardiomyocytes.
Overexpression of VCP prevents TAC-induced cardiac remodeling and heart failure via a pro-survival mechanism involving mTORC2 signaling pathway.