Alterations in G Protein and MAP Kinase Signaling Pathways During Cardiac Remodeling in Hypertension and Heart Failure
- 1 April 2003
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 41 (4), 968-977
- https://doi.org/10.1161/01.hyp.0000062465.60601.cc
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, Gα q and Gα 12 protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, Gβ and Gα 13 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.Keywords
This publication has 24 references indexed in Scilit:
- Myocyte Redistribution of GRK2 and GRK5 in Hypertensive, Heart-Failure–Prone RatsHypertension, 2002
- Src and Multiple MAP Kinase Activation in Cardiac Hypertrophy and Congestive Heart Failure Under Chronic Pressure-overload: Comparison with Acute Mechanical StretchJournal of Molecular and Cellular Cardiology, 2001
- Decreased p38 MAPK Activity in End-Stage Failing Human Myocardium: p38 MAPK α is the Predominant Isoform Expressed in Human HeartJournal of Molecular and Cellular Cardiology, 2001
- Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertensionThe FASEB Journal, 2001
- Gα13 stimulates gene expression and increases cell size in cultured neonatal rat ventricular myocytesCardiovascular Research, 1999
- Cell growth control by G protein-coupled receptors: from signal transduction to signal integrationOncogene, 1998
- Mitogen-activated protein kinase pathwaysCurrent Opinion in Cell Biology, 1997
- G Protein–Coupled Receptors and Receptor Kinases: From Molecular Biology to Potential Therapeutic ApplicationsNature Biotechnology, 1996
- The small GTP-binding proteins Rac1 and Cdc42regulate the activity of the JNK/SAPK signaling pathwayCell, 1995
- G PROTEINS: TRANSDUCERS OF RECEPTOR-GENERATED SIGNALSAnnual Review of Biochemistry, 1987