Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model.

Xiaonan Sun,Gangjian Qin,Ning Zhou,Hongyu Qiu,Lo Lai,Shaunrick Stoll,Wenqian Wu,Ben Ma

doi:10.3390/cells10112891

Abstract

Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal. We generated a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse to determine the effects of impaired VCP activity on the heart. Using echocardiography, we showed that cardiac-specific overexpression of DN-VCP induced a remarkable cardiac dilation and progressively declined cardiac function during the aging transition. Mechanistically, DN-VCP did not affect the endogenous VCP (EN-VCP) expression but significantly reduced cardiac ATPase activity in the DN-VCP TG mouse hearts, indicating a functional inhibition. DN-VCP significantly impaired the aging-related cytoplasmic/nuclear shuffling of EN-VCP and its co-factors in the heart tissues and interrupted the balance of the VCP-cofactors interaction between the activating co-factors, ubiquitin fusion degradation protein 1 (UFD-1)/nuclear protein localization protein 4 (NPL-4) complex, and its inhibiting co-factor P47, leading to the binding preference with the inhibitory co-factor, resulting in functional repression of VCP. This DN-VCP TG mouse provides a unique functional-inactivation model for investigating VCP in the heart in physiological and pathological conditions.

Highlights

Valosin-containing protein (VCP), known as p97 in mammals and CDC48 inS. cerevisiae, is a member of the type II AAA (ATPases Associated with various cellularActivities) family, which is ubiquitously expressed in cells [1,2,3]
The results showed that NPL4, ubiquitin fusion degradation protein 1 (UFD-1), and P47 interacted with full-length VCP (FL-VCP) but not with dominant-negative VCP (DN-VCP) (Figure 5a)
The present study provides additional evidence indicating that VCP is an essential regulator of cardiac function in physiological conditions, which has been uncharacterized previously

Summary

Introduction

Valosin-containing protein (VCP), known as p97 in mammals and CDC48 inS. cerevisiae, is a member of the type II AAA (ATPases Associated with various cellularActivities) family, which is ubiquitously expressed in cells [1,2,3]. Cardiac-specific overexpressing VCP protects mouse hearts against pressure-overload-induced pathological hypertrophy [15,16,17] and heart failure [18], and it protects against stress-induced cardiomyocyte death in vitro and reduced ischemic injury in vivo [19,20,21]. These results together indicated that VCP plays a critical protective role in the heart under stress conditions. Since the VCP knockout in mice is embryonically lethal [22], functional inactivation of VCP would provide a powerful approach to determine whether VCP is necessarily required for cardiac function in the heart

Methods

Results

Conclusion