Vitamin D3-up-regulated protein-1 is a stress-responsive gene that regulates cardiomyocyte viability through interaction with thioredoxin

被引:148
作者
Wang, YL [1 ]
De Keulenaer, GW [1 ]
Lee, RT [1 ]
机构
[1] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, Cambridge, MA 02139 USA
关键词
D O I
10.1074/jbc.M202133200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:26496 / 26500
页数:5
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