Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities

Abstract

Valosin-containing protein (VCP/p97) is a member of the conserved type II AAA+ (ATPases associated with diverse cellular activities) family of proteins with multiple biological functions, especially in protein homeostasis. Mutations in VCP/p97 are reportedly related to unique autosomal dominant diseases, which may worsen cardiac function. Although the structure of VCP/p97 has been clearly characterized, with reports of high abundance in the heart, research focusing on the molecular mechanisms underpinning the roles of VCP/p97 in the cardiovascular system has been recently undertaken over the past decades. Recent studies have shown that VCP/p97 deficiency affects myocardial fibers and induces heart failure, while overexpression of VCP/p97 eliminates ischemia/reperfusion injury and relieves pathological cardiac hypertrophy caused by cardiac pressure overload, which is related to changes in the mitochondria and calcium overload. However, certain studies have drawn opposing conclusions, including the mitigation of ischemia/reperfusion injury via inhibition of VCP/p97 ATPase activity. Nevertheless, these emerging studies shed light on the role of VCP/p97 and its therapeutic potential in cardiovascular diseases. In other words, VCP/p97 may be involved in the development of cardiovascular disease, and is anticipated to be a new therapeutic target. This review summarizes current findings regarding VCP/p97 in the cardiovascular system for the first time, and discusses the role of VCP/p97 in cardiovascular disease.

CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo

“…Elevated levels of phosphorylated RPS6 are correlated with increased activity of the mTORC1 (mechanistic target of rapamycin complex 1) pathway. Under physiological conditions, Vcp is known to inhibit mTORC1 signaling [ 28 , 29 , 30 ]. Interestingly, we found significant upregulation of phosphorylated RPS6 (pRPS6) ( Figure 4 B,E) (N = 4; p = 0.0286) in vcp ex3/ex3 mutant embryos compared to controls, whereas total RPS6 protein levels were unchanged in vcp ex3/ex3 mutant embryos ( Figure 4 B,D) (N = 4; p = 0.3143), suggesting activated mTOR signaling and thereby the repression of autophagy [ 31 ].…”

Valosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication

“…The disruption of protein homeostasis has been proved to involve in various cardiac diseases, which includes heart failure, myocardial infarction, and diabetic cardiomyopathy (22). As an important maintainer of protein homeostasis in cardiovascular system, VCP has been suggested to have a protective role toward ischemia-reperfusion injury and VD (23)(24)(25). In our recent study, a significant increase in serum VCP concentration was observed in early myocardial ischemia-induced SCD cases, which further verified the activation of VCP expression toward acute myocardial ischemia (26).…”