Abstract 423: The Valosin-containing Protein Attenuates Chronic Pressure Overload-induced Cardiac Remodeling and Heart Failure via Activating mTORC2 Pathway

Abstract

Aims: 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 . Methods and Results: 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. Conclusion: Overexpression of VCP prevents TAC-induced cardiac remodeling and heart failure via a pro-survival mechanism involving mTORC2 signaling pathway.