Pharmacological Inhibition of Valosin-Containing Protein (VCP) Triggers Cardiac Hypertrophy and Heart Failure in Vivo.

Abstract

Valosin-containing protein (VCP) is a crucial ATPase involved in maintaining protein homeostasis through the ubiquitin-proteasome system (UPS) and endoplasmic reticulum-associated degradation (ERAD). Dysregulation of VCP has been implicated in neurodegenerative diseases, cancer, and myopathies, and has also been associated with cardiac dysfunction and hypertrophy remodeling. The roles of VCP in the context of cardiomyocyte function and protein homeostasis are still poorly understood. This study examines the effects of pharmacological Vcp inhibition in zebrafish embryos using CB-5083, a selective Vcp ATPase inhibitor. CB-5083-treated embryos exhibited cardiac and skeletal muscle abnormalities, including myofibrillar disorganization, impaired cardiac function, and locomotor defects, closely resembling CRISPR/Cas9-mediated vcp knockout phenotypes. Early developmental inhibition (24-72 hpf) led to severe cardiac impairment and apoptosis, whereas inhibition during late development (72-120 hpf) induced ventricular hypertrophy with preserved contractile function, suggesting a developmental stage-dependent effect. Furthermore, Vcp inhibition was associated with markers of disrupted proteostasis, suggesting UPS dysfunction and ER stress activation. These findings establish a zebrafish model of VCP-related cardiomyopathy, highlight its role in cardiac proteostasis and hypertrophic remodeling, and provide novel insights into disease mechanisms and potential therapeutic targets.