Published Online
on March 3, 2008

A more recent version of this article appeared on March 18, 2008

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Submitted on November 14, 2007
Accepted on January 22, 2008

Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress

Brent R. DeGeorge Jr BS, Erhe Gao MD, PhD, Matthieu Boucher PhD, Leif E. Vinge MD, PhD, Jeffrey S. Martini BS, Philip W. Raake MD, J. Kurt Chuprun PhD, David M. Harris PhD, Gilbert W. Kim BS, Stephen Soltys BS, Andrea D. Eckhart PhD, and Walter J. Koch PhD^*

From the Center for Translational Medicine (B.R.D., E.G., M.B., L.E.V., J.S.M., P.W.R., J.K.C., D.M.H., G.W.K., S.S., A.D.E., W.J.K.), George Zallie and Family Laboratory of Cardiovascular Gene Therapy (B.R.D., E.G., M.B., L.E.V., J.S.M., P.W.R., J.K.C., G.W.K., S.S., W.J.K.), and Eugene Feiner Laboratory of Vascular Biology and Thrombosis (D.M.H., A.D.E.), Thomas Jefferson University, Philadelphia, Pa, and Institute for Surgical Research, University of Oslo, Oslo, Norway (L.E.V.).

^* To whom correspondence should be addressed. E-mail: walter.koch{at}jefferson.edu.

Background—A salient characteristic of dysfunctional myocardium progressing to heart failure is an upregulation of the adenylyl cyclase inhibitory guanine nucleotide (G) protein subunit, G_i2. It has not been determined conclusively whether increased Gi activity in the heart is beneficial or deleterious in vivo. Gi signaling has been implicated in the mechanism of cardioprotective agents; however, no in vivo evidence exists that any of the G subunits are cardioprotective. We have created a novel molecular tool to specifically address the role of Gi proteins in normal and dysfunctional myocardium.

Methods and Results—We have developed a class-specific Gi inhibitor peptide, GiCT, composed of the region of G_i2 that interacts specifically with G protein–coupled receptors. GiCT inhibits Gi signals specifically in vitro and in vivo, whereas Gs and Gq signals are not affected. In vivo expression of GiCT in transgenic mice effectively causes a "functional knockout" of cardiac G_i2 signaling. Inducible, cardiac-specific GiCT transgenic mice display a baseline phenotype consistent with nontransgenic mice. However, when subjected to ischemia/reperfusion injury, GiCT transgenic mice demonstrate a significant increase in infarct size compared with nontransgenic mice (from 36.9±2.5% to 50.9±4.3%). Mechanistically, this post-ischemia/reperfusion phenotype includes increased myocardial apoptosis and resultant decreased contractile performance.

Conclusions—Overall, our results demonstrate the in vivo utility of GiCT to dissect specific mechanisms attributed to Gi signaling in stressed myocardium. Our results with GiCT indicate that upregulation of G_i2 is an adaptive protective response after ischemia to shield myocytes from apoptosis.

Key words: apoptosis • heart diseases • myocardial infarction • signal transduction

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