This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 41/4/968    most recent 01.HYP.0000062465.60601.CCv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kacimi, R. Articles by Gerdes, A. M. Search for Related Content PubMed PubMed Citation Articles by Kacimi, R. Articles by Gerdes, A. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Heart Failure High Blood Pressure Related Collections Biochemistry and metabolism Congestive Hypertrophy Remodeling Signal transduction Genetics of cardiovascular disease ACE/Angiotension receptors Animal models of human disease Cell signalling/signal transduction Growth factors/cytokines Heart failure - basic studies Hypertension - basic studies

(Hypertension. 2003;41:968.)
© 2003 American Heart Association, Inc.

Scientific Contributions

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

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

Correspondence to Rachid Kacimi, PhD, Cardiovascular Research Institute, University of South Dakota School of Medicine, 1400 West 22nd St, Sioux Falls, SD 57105. E-mail rkacimi{at}usd.edu

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, Gß 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

This article has been cited by other articles:

				D. P. Del Re, S. Miyamoto, and J. H. Brown RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte Apoptosis J. Biol. Chem., March 16, 2007; 282(11): 8069 - 8078. [Abstract] [Full Text] [PDF]

				S. Keidar, M. Kaplan, and A. Gamliel-Lazarovich ACE2 of the heart: From angiotensin I to angiotensin (1-7) Cardiovasc Res, February 1, 2007; 73(3): 463 - 469. [Abstract] [Full Text] [PDF]

				E. Bisping, S. Ikeda, S. W. Kong, O. Tarnavski, N. Bodyak, J. R. McMullen, S. Rajagopal, J. K. Son, Q. Ma, Z. Springer, et al. Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure PNAS, September 26, 2006; 103(39): 14471 - 14476. [Abstract] [Full Text] [PDF]

				G. Foldes, S. Vajda, Z. Lako-Futo, B. Sarman, R. Skoumal, M. Ilves, R. deChatel, I. Karadi, M. Toth, H. Ruskoaho, et al. Distinct modulation of angiotensin II-induced early left ventricular hypertrophic gene programming by dietary fat type J. Lipid Res., June 1, 2006; 47(6): 1219 - 1226. [Abstract] [Full Text] [PDF]

				D. Stilli, L. Bocchi, R. Berni, M. Zaniboni, F. Cacciani, C. Chaponnier, E. Musso, G. Gabbiani, and S. Clement Correlation of {alpha}-skeletal actin expression, ventricular fibrosis and heart function with the degree of pressure overload cardiac hypertrophy in rats Exp Physiol, May 1, 2006; 91(3): 571 - 580. [Abstract] [Full Text] [PDF]

				S. M. Dallabrida, N. Ismail, J. R. Oberle, B. E. Himes, and M. A. Rupnick Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins Circ. Res., March 4, 2005; 96(4): e8 - e24. [Abstract] [Full Text] [PDF]

				M. R. Dent, N. S. Dhalla, and P. S. Tappia Phospholipase C gene expression, protein content, and activities in cardiac hypertrophy and heart failure due to volume overload Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H719 - H727. [Abstract] [Full Text] [PDF]

				A. Nishiyama, H. Kobori, T. Fukui, G.-X. Zhang, L. Yao, M. Rahman, H. Hitomi, H. Kiyomoto, T. Shokoji, S. Kimura, et al. Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A-Dependent Hypertension Hypertension, October 1, 2003; 42(4): 754 - 760. [Abstract] [Full Text] [PDF]