Published Online
on March 17, 2003

A more recent version of this article appeared on April 1, 2003

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Submitted on October 9, 2002
Revised on November 7, 2002

Alterations in G Protein and MAP Kinase Signaling Pathways During Cardiac Remodeling in Hypertension and Heart Failure

Rachid Kacimi^* and Anthony Martin Gerdes

From the Cardiovascular Research Institute, University of South Dakota School of Medicine, and Sioux Valley Hospitals and Health Systems, Sioux Falls, SD.

^* To whom correspondence should be addressed. E-mail: rkacimi{at}usd.edu.

Abstract--The present study was undertaken to elucidate the G-protein and mitogen-activated kinase (MAP kinase) coupled signaling profile in a genetic model of hypertension and congestive heart failure (CHF) that mimics similar disease in humans. At the receptor level, Ang II type 1 receptor (AT_1R) increased in left ventricular hypertrophy (LVH) and reverted to normal in CHF, whereas there was a downregulation of the Ang II type 2 receptor (AT_2R) in CHF. At the transducer level, G_q and G₁₂ protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, G and G₁₃ protein content were markedly upregulated in CHF. Furthermore, using phospho-specific antibodies in Western blots and in vitro kinase assays, we found at the effector level an upregulation of the small G-protein Rac1 activity during LVH but a decrease during CHF. In parallel, small G-protein Rho activity was significantly increased during LVH but was unchanged in failure. We found at the downstream level that MAP kinase isoforms extracellular signal regulated-kinase (ERK1/2), big mitogen-activated kinase (BMK1/ERK5), C-jun N-terminal-activated kinase (JNKs/SAPKs), and stress-activated kinase (p38) bioactivities were increased during LVH. During CHF, ERK1/2 and JNK1/2 kinase activities were decreased, whereas BMK1/ERK5 kinase activity reverted to normal values. In conclusion, this study demonstrates, for the first time, multistep alterations of G-protein and MAP kinase signaling pathways in LVH and progression to failure in a genetic model of hypertension and failure.

Key words: G proteins • signal transduction • hypertension, genetic • hypertrophy • heart failure

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