Genomic characterization reveals novel mechanisms underlying the valosin-containing protein-mediated cardiac protection against heart failure

Abstract

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.

Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

“…The regulatory mechanism underlying the cardiac protection of VCP involved the potential effects at multiple levels including the upstream transcription factors, gene expression and the alternative splicing, which constitute an integrative gene network, inhibiting the hypertrophy signaling and promoting mitochondrial function in the stressed hearts. We also assess the RNA-seq data quality using the ERCC spiked-in control 37 .…”

“…RNA-seq libraries were sequenced on Illumina HiSeq 4000 at the Loma Linda University Center for Genomics, 150 × 2 bp, paired-end. We also assess the RNA-seq data quality using the ERCC spiked-in control 37 .…”

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

“…Fourth, studies showed that the increase in mitochondrial sirtuin-3, a member of the sirtuins’ family, can attenuate cardiac hypertrophy by decreasing oxidative stress [ 104 ]. Recent studies also showed that deficiency of a valosin-containing protein (VCP) in the heart is associated with the pressure overload-induced pathologic cardiac hypertrophy and heart failure, likely through a mechanism by the activation of oxidative stress and the increased ROS production [ 105 , 106 ].…”

Multiple Feature Selection Strategies Identified Novel Cardiac Gene Expression Signature for Heart Failure

“…Approximately 26 million patients worldwide are suffering from heart failure, and the society faces the long-term great stresses on patients, medical stuff, and medical systems ( Bowen et al, 2020 ). About 17–45% of patients with heart failure die within 1 year, and the majority die within 5 years admitted to a hospital in worldwide ( Davison and Cotter, 2015 ; Zhou et al, 2020 ). However, the survival rates for patients with HF have improved in many parts of the world in recent years along with the advanced therapies and patient management systems.…”

“… Tan et al (2002) used microarrays to describe gene expression fingerprints of HF etiologies based on seven non-failing human hearts and eight failing human hearts with a diagnosis of end-stage dilated cardiomyopathy. Zhou et al (2020) proposed that valosin-containing protein could protect the heart against pressure overload-induced heart failure using RNA-Seq and a comprehensive bioinformatics analysis. Kittleson et al (2004) used microarrays of 48 myocardial samples and gene expression profiling to predict biomarkers in determining prognosis and response to therapy in HF precisely.…”