Abstract
Aims: Valosin-containing protein (VCP) participates in signaling pathways essential for cell homeostasis in multiple tissues, yet its role in mammalian heart remains largely unknown. Our recent studies showed that overexpression of VCP protects cardiomyocytes from stress- induced cell death in both in vitro and in vivo , however, it is unknown which target genes and pathways are regulated by VCP through which the heart may be protected from stress-induced injury. Here we provided the first in vivo evidence of the VCP-regulated target genes by microarray gene expression profiling in a transgenic mouse model. Methods and results: We generated a transgenic (TG) mouse that over-expressed 3.5 fold VCP specifically in the heart. Total RNA extracted from the heart tissues from both adult VCP TG and their litter-matched wild type (WT) mice (N=4/group) was assayed by using Affymetrix Mouse Genome 430 2.0 Array, which interrogates over 39,000 transcripts. Differentially expressed genes (DEGs) were defined by p-value ≤ 0.05 and FC (fold change) ≥ 1.5, and totally 581 DEGs were identified between VCP TG and WT. Applying a more stringent criteria (FDR ≤ 0.05 and FC ≥ 1.5), we identified 21 upregulated and 28 downregulated genes in VCP TG mouse hearts compared to WT. Among the top DEGs, there is a significant up-regulation in the genes regulating the stress response and oxidation in VCP TG versus WT, such as a kinase interacting protein by 2.6 folds which is a key regulator of cardiac stress; glutathione peroxidase 1 by 2.2 folds which is an antioxidant enzyme and anti-apoptotic mediators: protein kinase C delta by 2.3 folds and B-cell lymphoma 2 by 2.7 folds. VCP TG mice also exhibits an upregulation in the genes involved in cellular structure and contractility, e.g., alpha 1 actin by 3.3 folds, myosin light chain 9 by 8.2 folds and Tropomyosin 2 by 4.5 folds which is a gene regulating the binding of myosin and actin. Other DEGs include the upregulated-genes regulating cellular amino acid metabolism such as pterin-4 alpha-carbinolamine dehydratase by 9.7folds, phosphatidic acid phosphatase 2c by 3.4 folds and sortilin 1 by 2.4 folds. Conclusion: Significant difference of gene regulation exists between VCP TG and WT in the heart, which may be the mechanism of VCP-mediated cardiac protection.
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