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Article

Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1

by
Xiaonan Sun
1,
Xicong Tang
1,2 and
Hongyu Qiu
1,2,3,*
1
Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA
2
Cardiovascular Translational Research Center, Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA
3
Clinical Translational Sciences (CTS) and Bio5 Institution, University of Arizona, Tucson, AZ 85721, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(12), 6445; https://doi.org/10.3390/ijms25126445
Submission received: 14 May 2024 / Revised: 6 June 2024 / Accepted: 8 June 2024 / Published: 11 June 2024
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)

Abstract

Valosin-containing protein (VCP), an ATPase-associated protein, is emerging as a crucial regulator in cardiac pathologies. However, the pivotal role of VCP in the heart under physiological conditions remains undetermined. In this study, we tested a hypothesis that sufficient VCP expression is required for cardiac development and physiological cardiac function. Thus, we generated a cardiac-specific VCP knockout (KO) mouse model and assessed the consequences of VCP suppression on the heart through physiological and molecular studies at baseline. Our results reveal that homozygous KO mice are embryonically lethal, whereas heterozygous KO mice with a reduction in VCP by ~40% in the heart are viable at birth but progressively develop heart failure and succumb to mortality at the age of 10 to 12 months. The suppression of VCP induced a selective activation of the mammalian target of rapamycin complex 1 (mTORC1) but not mTORC2 at the early age of 12 weeks. The prolonged suppression of VCP increased the expression (by ~2 folds) and nuclear translocation (by >4 folds) of protein phosphatase 1 (PP1), a key mediator of protein dephosphorylation, accompanied by a remarked reduction (~80%) in AKTSer473 phosphorylation in VCP KO mouse hearts at a later age but not the early stage. These temporal molecular alterations were highly associated with the progressive decline in cardiac function. Overall, our findings shed light on the essential role of VCP in the heart under physiological conditions, providing new insights into molecular mechanisms in the development of heart failure.
Keywords: valosin-containing protein; heart failure; mTOR complex; protein phosphatase 1 valosin-containing protein; heart failure; mTOR complex; protein phosphatase 1

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MDPI and ACS Style

Sun, X.; Tang, X.; Qiu, H. Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1. Int. J. Mol. Sci. 2024, 25, 6445. https://doi.org/10.3390/ijms25126445

AMA Style

Sun X, Tang X, Qiu H. Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1. International Journal of Molecular Sciences. 2024; 25(12):6445. https://doi.org/10.3390/ijms25126445

Chicago/Turabian Style

Sun, Xiaonan, Xicong Tang, and Hongyu Qiu. 2024. "Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1" International Journal of Molecular Sciences 25, no. 12: 6445. https://doi.org/10.3390/ijms25126445

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