Vitamin D(3)-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 D(3)-up-regulated protein-1 regulates thioredoxin in conditions of biomechanical or oxidative stress and critically regulates cardiomyocyte viability. Expression of vitamin D(3)-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 D(3)-up-regulated protein-1 gene expression was blocked by N-acetylcysteine. The half-life of vitamin D(3)-up-regulated protein-1 transcripts in cardiomyocytes was only 1.1 h and remained unchanged after mechanical stimulation, suggesting that rapid responses in vitamin D(3)-up-regulated protein-1 gene expression occur through transcriptional control. Vitamin D(3)-up-regulated protein-1 down-regulation by strain or hydrogen peroxide led to increased thioredoxin activity, whereas adenovirus-mediated overexpression of vitamin D(3)-up-regulated protein-1 suppressed thioredoxin activity. Overexpression of vitamin D(3)-up-regulated protein-1 but not of thioredoxin induced cardiomyocyte apoptosis. Furthermore, overexpression of vitamin D(3)-up-regulated protein-1 sensitized cells to hydrogen peroxide-induced apoptosis, whereas overexpression of thioredoxin protected against injury. These data identify vitamin D(3)-up-regulated protein-1 as a key stress-responsive inhibitory switch of thioredoxin activity in cardiomyocytes and demonstrate that the vitamin D(3)-up-regulated protein-1/thioredoxin axis has an important role in the preservation of cellular viability.
Wang
Yanlin
Y
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Cambridge, Massachusetts 02139, USA.
De Keulenaer
Gilles W
GW
Lee
Richard T
RT
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002470:Cell Survival; D015536:Down-Regulation; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013879:Thioredoxins / Q000378:metabolism*
D002352:Carrier Proteins; D012333:RNA, Messenger; C486715:TXNIP protein, human; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D000111:Acetylcysteine