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J. Biol. Chem., Vol. 283, Issue 48, 33384-33393, November 28, 2008

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Removal of the N-terminal Extension of Cardiac Troponin I as a Functional Compensation for Impaired Myocardial β-Adrenergic Signaling^*

Han-Zhong Feng¹, Min Chen, Lee S. Weinstein, and Jian-Ping Jin²

From the Section of Molecular Cardiology, Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois 60201 and the Signal Transduction Section, Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

Although β-adrenergic stimuli are essential for myocardial contractility, β-blockers have a proven beneficial effect on the treatment of heart failure, but the mechanism is not fully understood. The stimulatory G protein -subunit (G_s) couples the β-adrenoreceptor to adenylyl cyclase and the intracellular cAMP response. In a mouse model of conditional G_s deficiency in the cardiac muscle (G_s-DF), we demonstrated heart failure phenotypes accompanied by increases in the level of a truncated cardiac troponin I (cTnI-ND) from restricted removal of the cTnI-specific N-terminal extension. To investigate the functional significance of the increase of cTnI-ND in G_s-DF cardiac muscle, we generated double transgenic mice to overexpress cTnI-ND in G_s-DF hearts. The overexpression of cTnI-ND in Gs-DF failing hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired β-adrenergic signaling, the aberrant expression of β-myosin heavy chain in adult G_s-DF but not control mouse hearts was reversed by cTnI overexpression. These data indicate that the up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired β-adrenergic signaling.

Received for publication, April 30, 2008 , and in revised form, September 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL-078773 and AR-048816 (to J.-P. J.) and by the Intramural Research Program of the National Institutes of Health, NIDDK. 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 A Ph.D. candidate in the Aerospace Physiology Graduate Program at Fourth Military Medical University, Xi'an, China.

² To whom correspondence should be addressed: Section of Molecular Cardiology, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL 60201. Tel.: 847-570-1960; Fax: 847-570-1865; E-mail: jpjin{at}northwestern.edu.

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