Here, researchers investigate the role of the VCP gene in producing cardiac hypertrophy as a response to hypertension, or high blood pressure. Blood vessels become stiff with age, the result of cross-linking, calcification, and dysfunction in the smooth muscle that controls contraction and dilation. This causes hypertension by breaking the finely balanced feedback systems that regulate blood pressure in response to environmental circumstances. Hypertension in turn causes cardiac hypertrophy: heart tissue expands inappropriately to become both larger and weaker. At the end of this road lies death due to heart failure or structural failure of critical blood vessels in a high pressure environment. Addressing the root causes would be the best way forward, but most research groups are more interested in controlling mechanisms at later stages of the process, such as VCP. Therapies based on this sort of work have the potential to produce some benefits, but nowhere near as comprehensively as reversal of vascular stiffness.
Pressure overload-induced cardiac hypertrophy, such as that caused by chronic hypertension, is a major independent risk factor for heart failure. Accumulating evidences from studies in patients and animal models suggest that cardiac hypertrophy induced by chronic pressure overload is not a compensatory but rather a maladaptive process. Despite intensive research efforts over several decades, the molecular mechanisms of hypertrophic heart failure are not fully understood. Therefore, it has become compulsory to identify novel targets involved in the pathogenesis of cardiac hypertrophy and its transition to heart failure.
Our previous studies identified valosin-containing protein (VCP) in the heart and showed that it is a critical mediator of cardiomyocyte survival under ischemic stress both in vitro and in vivo. However, the role of VCP in cardiac growth or hypertrophy under stress conditions was completely unknown. We observed that VCP expression was significantly down-regulated in the hypertrophic left ventricle (LV) tissues of both hypertensive rats and transverse aortic constriction (TAC)-induced pressure-overloaded mice. These findings demonstrated a strong link between down-regulation of VCP expression and hypertensive cardiomyopathy. Reciprocally, cardiac-specific overexpression of VCP in a transgenic (TG) mouse significantly attenuated the pressure overload-induced cardiac hypertrophy. These data together suggested that VCP plays a critical role in pressure overload-induced cardiac hypertrophy.
Direct evidence of VCP's cardioprotective effect was shown in an in vitro study where VCP was downregulated in AngII-induced hypertrophic cardiomyocytes in a dose- and time-dependent manner, whereas the overexpression of VCP prevented AngII-induced cardiomyocyte hypertrophy. In addition, we also found that VCP plays a dual role on the regulation of the mechanistic target of rapamycin (mTOR) signaling in the heart: activating the survival-promoting mTORC2 but repressing the stress-induced growth-promoting mTORC1. These data suggested that VCP acts as a negative regulator of mTORC1 under stress of pressure overload. These selective effects of VCP on mTORC1 and mTORC2 are different from that of other mTOR regulators identified in the heart, such as rapamycin, and also distinct from the function of VCP observed in other tissues. Moreover, VCP suppressed mTORC1 signaling only under the stress of TAC but not at the baseline condition.
Our data collectively concluded that pressure overload reduced VCP expression in the heart which attenuated the inhibitive effect of VCP on mTORC1 signaling, subsequently promoting the pro-growth pathway and resulting in cardiac hypertrophy. These findings bring new insights to the regulatory effects of VCP in the heart and also lead to a new therapeutic target for pressure overload-induced cardiac pathogenesis.