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J. Biol. Chem., Vol. 283, Issue 10, 5996-6004, March 7, 2008

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Down-regulation of Catalase and Oxidative Modification of Protein Kinase CK2 Lead to the Failure of Apoptosis Repressor with Caspase Recruitment Domain to Inhibit Cardiomyocyte Hypertrophy^*

Iram Murtaza¹, Hong-Xia Wang¹, Xue Feng, Natalia Alenina, Michael Bader, Bellur S. Prabhakar^¶, and Pei-Feng Li²

From the Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, the ^¶College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, and the Max-Delbruck-Center for Molecular Medicine, Berlin 13125, Germany

Cardiac hypertrophy is regulated by a complex interplay of pro- and anti-hypertrophic factors. Here, we report a novel anti-hypertrophic pathway composed of catalase, protein kinase CK2 (CK2), and apoptosis repressor with caspase recruitment domain (ARC). Our results showed that ARC phosphorylation levels, CK2 activity, and catalase expression levels were decreased in the hearts of the angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli, including phenylephrine, tumor necrosis factor-, and angiotensin II. To understand the role of ARC in hypertrophy, we observed that enforced expression of ARC could inhibit hypertrophy. Knockdown of endogenous ARC or inhibition of its phosphorylation could sensitize cardiomyocytes to undergoing hypertrophy. The phosphorylatable, but not the nonphosphorylatable, ARC could inhibit hypertrophy. Thus, ARC is able to inhibit hypertrophy in a phosphorylation-dependent manner. In exploring the molecular mechanism by which CK2 activity is reduced, we found that CK2 was carbonylated in angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli. The decrease in catalase expression led to an elevated level of reactive oxygen species. The latter oxidatively modified CK2, resulting in its carbonylation. CK2 lost its catalytic activity upon carbonylation. ARC is phosphorylated by CK2, and ARC phosphorylation levels were reduced as a consequence of the decrease of CK2 activity. To understand the molecular mechanism by which ARC inhibits hypertrophy, we observed that ARC could inhibit the activation of mitochondrial permeability transition. These results suggest that catalase, CK2, and ARC constitute an anti-hypertrophic pathway in the heart.

Received for publication, August 6, 2007 , and in revised form, November 27, 2007.

^* This work was supported by the National Natural Science Foundation of China (Grant 30730045), the National Basic Research Program of China (973 Program, 2007CB512000), and the American Heart Association. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 86-10-6480-7176; Fax: 86-10-6480-7718; E-mail: peifli{at}ioz.ac.cn.

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