Vitamin D₃-up-regulated Protein-1 Is a Stress-responsive Gene That Regulates Cardiomyocyte Viability through Interaction with Thioredoxin*

The protein-disulfide reductase thioredoxin is critical for redox signaling during apoptosis and growth. In this study, we demonstrate that vitamin D₃-up-regulated protein-1 regulates thioredoxin in conditions of biomechanical or oxidative stress and critically regulates cardiomyocyte viability. Expression of vitamin D₃-up-regulated protein-1 but not of thioredoxin in rat cardiomyocytes was rapidly suppressed by biomechanical strain or hydrogen peroxide at both mRNA and protein levels. Mechanical suppression of vitamin D₃-up-regulated protein-1 gene expression was blocked by N-acetylcysteine. The half-life of vitamin D₃-up-regulated protein-1 transcripts in cardiomyocytes was only 1.1 h and remained unchanged after mechanical stimulation, suggesting that rapid responses in vitamin D₃-up-regulated protein-1 gene expression occur through transcriptional control. Vitamin D₃-up-regulated protein-1 down-regulation by strain or hydrogen peroxide led to increased thioredoxin activity, whereas adenovirus-mediated overexpression of vitamin D₃-up-regulated protein-1 suppressed thioredoxin activity. Overexpression of vitamin D₃-up-regulated protein-1 but not of thioredoxin induced cardiomyocyte apoptosis. Furthermore, overexpression of vitamin D₃-up-regulated protein-1 sensitized cells to hydrogen peroxide-induced apoptosis, whereas overexpression of thioredoxin protected against injury. These data identify vitamin D₃-up-regulated protein-1 as a key stress-responsive inhibitory switch of thioredoxin activity in cardiomyocytes and demonstrate that the vitamin D₃-up-regulated protein-1/thioredoxin axis has an important role in the preservation of cellular viability.