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J. Biol. Chem., Vol. 280, Issue 47, 39394-39402, November 25, 2005

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Catalytic Degradation of Vitamin D Up-regulated Protein 1 mRNA Enhances Cardiomyocyte Survival and Prevents Left Ventricular Remodeling after Myocardial Ischemia^*

From the Departments of Surgery and Medicine, Columbia University Medical Center, New York, New York 10032

Vitamin D3 up-regulated protein 1 (VDUP1) is a key mediator of oxidative stress on various cellular processes via downstream effects on apoptosis signaling kinase 1 (ASK1) and p38 mitogen-activated protein kinase (MAPK). Here, we report that VDUP1 expression is significantly increased in rat hearts following acute myocardial ischemia, suggesting it may have important regulatory effects on cardiac physiological processes during periods of oxidative stress. Transfection of H9C2 cardiomyoblasts with a sequence-specific VDUP1 DNA enzyme to down-regulate VDUP1 mRNA expression significantly reduced apoptosis and enhanced cell survival under conditions of H₂O₂ stress, and these effects involved inhibition of ASK1 activity. Direct intracardiac injection of the DNA enzyme at the time of acute myocardial infarction reduced myocardial VDUP1 mRNA expression and resulted in prolonged reduction in cardiomyocyte apoptosis and ASK1 activity. Moreover, down-regulation of VDUP1 was accompanied by significant reduction in cardiac expression of pro-collagen type I 2 mRNA level, as well as marked reduction in myocardial scar formation. These features were accompanied by significant improvement in cardiac function. Together, these results suggest a direct role for VDUP1 in the adverse effects of ischemia and oxidative stress on cardiomyocyte survival, left ventricular collagen deposition, and cardiac function. Strategies to inhibit VDUP1 expression and/or function during acute ischemic events may be beneficial to cardiac functional recovery and prevention of left ventricular remodeling.

Received for publication, March 17, 2005 , and in revised form, September 8, 2005.

^* This work was supported in part by National Institutes of Health Grants RFA-HL-02-017 and RFA-AG-01-006. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Department of Medicine, University of Melbourne, Victoria 3065, Australia.

³ Present address: Department of Medicine, Monash University, Victoria 3181, Australia.

¹ To whom correspondence may be addressed: P&S 14-402, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-1614; Fax: 212-305-8145; E-mail: gx15{at}columbia.edu.

⁴ To whom correspondence may be addressed: P&S 14-402, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-1614; Fax: 212-305-8145; E-mail: si5{at}columbia.edu.

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