Genomic characterization reveals novel mechanisms underlying the valosin-containing protein-mediated cardiac protection against heart failure
Ning Zhou,
Xin Chen,
Jing Xi,
Ben Ma,
Christiana Leimena,
Shaunrick Stoll,
Gangjian Qin,
Charles Wang,
Hongyu Qiu
Affiliations
Ning Zhou
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA; Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
Xin Chen
Center for Genomics & Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA
Jing Xi
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA
Ben Ma
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA; Center of Molecular and Translational Medicine, Institution of Biomedical Science, Georgia State University, Atlanta, GA, 30303, USA
Christiana Leimena
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA
Shaunrick Stoll
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA
Gangjian Qin
Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
Charles Wang
Center for Genomics & Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA; Corresponding author. Center for Genomics, Department of Basic Sciences, School of Medicine, Loma Linda University, 11021 Campus Street, AH 120/104, Loma Linda, CA, 92350, USA.
Hongyu Qiu
Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA; Center of Molecular and Translational Medicine, Institution of Biomedical Science, Georgia State University, Atlanta, GA, 30303, USA; Corresponding author. Center of Molecular and Translational Medicine, Institution of Biomedical Science, Georgia State University, Petit Research Center, Room 588, 100 Piedmont Ave, Atlanta, GA, 30303, USA.
Chronic hypertension is a key risk factor for heart failure. However, the underlying molecular mechanisms are not fully understood. Our previous studies found that the valosin-containing protein (VCP), an ATPase-associated protein, was significantly decreased in the hypertensive heart tissues. In this study, we tested the hypothesis that restoration of VCP protected the heart against pressure overload-induced heart failure. With a cardiac-specific transgenic (TG) mouse model, we showed that a moderate increase of VCP was able to attenuate chronic pressure overload-induced maladaptive cardiac hypertrophy and dysfunction. RNA sequencing and a comprehensive bioinformatic analysis further demonstrated that overexpression of VCP in the heart normalized the pressure overload-stimulated hypertrophic signals and repressed the stress-induced inflammatory response. In addition, VCP overexpression promoted cell survival by enhancing the mitochondria resistance to the oxidative stress via activating the Rictor-mediated-gene networks. VCP was also found to be involved in the regulation of the alternative splicing and differential isoform expression for some genes that are related to ATP production and protein synthesis by interacting with long no-coding RNAs and histone deacetylases, indicating a novel epigenetic regulation of VCP in integrating coding and noncoding genomic network in the stressed heart. In summary, our study demonstrated that the rescuing of a deficient VCP in the heart could prevent pressure overload-induced heart failure by rectifying cardiac hypertrophic and inflammatory signaling and enhancing the cardiac resistance to oxidative stress, which brought in novel insights into the understanding of the mechanism of VCP in protecting patients from hypertensive heart failure.
