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J. Biol. Chem., Vol. 281, Issue 40, 29988-29992, October 6, 2006

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Reversible Heart Failure in G_q Transgenic Mice^*

Ya-Ping Jiang, Lisa M. Ballou, Zhongju Lu^¶, Li Wan, Damon J. Kelly^||, Ira S. Cohen^¶, and Richard Z. Lin^¶1

From the Department of Medicine, the ^¶Department of Physiology and Biophysics and the Institute of Molecular Cardiology, and the ^||Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794 and the Department of Veterans Affairs Medical Center, Northport, New York 11768

For many patients with cardiac insufficiency, the disease progresses inexorably to organ dilatation, pump failure, and death. Although there are examples of reversible heart failure in man, our understanding of how the myocardium repairs itself is limited. A well defined animal model of reversible heart failure would allow us to better investigate these restorative processes. Receptors that activate G_q, a signal transduction molecule in the heterotrimeric G protein superfamily, are thought to play a key role in the development of heart failure. We demonstrated previously that mice expressing a recombinant G_q protein, the activity of which can be turned on or off at will in cardiac myocytes, develop a dilated cardiomyopathy with generalized edema and heart failure following activation of the protein (Fan, G., Jiang, Y.-P., Lu, Z., Martin, D. W., Kelly, D. J., Zuckerman, J. M., Ballou, L. M., Cohen, I. S., and Lin, R. Z. (2005) J. Biol. Chem. 280, 40337-40346). Here we report that the contractile dysfunction and pathological structural changes in the myocardium improved significantly after termination of the G_q signal, even in animals with overt heart failure. Abnormalities in two proteins that regulate Ca²⁺ handling in myocytes, phospholamban and the voltage-dependent L-type Ca²⁺ channel, were also reversed, as was the increased expression of genes that are associated with heart failure. These results indicate that the heart has a substantial reparative capacity if the molecular signals responsible for the myocardial dysfunction can be identified and blocked.

Received for publication, May 16, 2006 , and in revised form, July 17, 2006.

^* This work was supported by a Merit Review Award from the Department of Veterans Affairs, a grant-in-aid from the American Heart Association, and by National Institutes of Health Grants DK62722 (to R. Z. L.) and HL28958 and HL67101 (to I. S. C.). 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 To whom correspondence should be addressed: Dept. of Medicine, Division of Hematology and Oncology, Stony Brook University, Stony Brook, NY 11794-8151. Tel.: 631-444-2059; Fax: 631-444-7530; E-mail: richard.lin{at}sunysb.edu.

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