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

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Developmental Biology

Background:

• Valosin-containing protein (VCP) is essential for protein homeostasis via the ubiquitin-proteasome system (UPS) and ERAD.
• VCP dysregulation is linked to neurodegenerative diseases, cancer, myopathies, and cardiac dysfunction.
• The specific roles of VCP in cardiomyocyte function and cardiac protein homeostasis remain unclear.

Purpose of the Study:

• To investigate the effects of pharmacological VCP inhibition on cardiac function and proteostasis in zebrafish embryos.
• To establish a zebrafish model for studying VCP-related cardiomyopathy and its underlying mechanisms.

Main Methods:

• Pharmacological inhibition of VCP ATPase activity using CB-5083 in zebrafish embryos.
• Assessment of cardiac and skeletal muscle morphology, cardiac function, and locomotor activity.
• Analysis of proteostasis markers, UPS dysfunction, and ER stress activation.

Main Results:

• CB-5083 treatment induced cardiac and skeletal muscle abnormalities, including myofibrillar disorganization and impaired cardiac function, mirroring VCP knockout phenotypes.
• Early VCP inhibition (24-72 hpf) caused severe cardiac impairment and apoptosis.
• Late VCP inhibition (72-120 hpf) resulted in ventricular hypertrophy with preserved contractile function, indicating developmental stage-dependent effects.
• VCP inhibition correlated with disrupted proteostasis, UPS dysfunction, and ER stress.

Conclusions:

• Pharmacological VCP inhibition in zebrafish provides a valuable model for VCP-related cardiomyopathy.
• VCP plays a critical role in maintaining cardiac proteostasis and regulating hypertrophic remodeling.
• These findings offer insights into VCP-related cardiac disease mechanisms and potential therapeutic strategies.