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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 41; no. 4; pp. 968 - 977
• Main Authors: Kacimi, Rachid, Gerdes, Anthony Martin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.04.2003; Hagerstown, MD Lippincott
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Disease Progression; Experimental diseases; GTP-Binding Proteins - metabolism; Heart Failure - enzymology; Heart Failure - metabolism; Heterotrimeric GTP-Binding Proteins - metabolism; Hypertension - enzymology; Hypertension - metabolism; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - metabolism; MAP Kinase Signaling System; Medical sciences; Mitogen-Activated Protein Kinases - metabolism; Monomeric GTP-Binding Proteins - metabolism; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Phosphoprotein Phosphatases - metabolism; Rats; Rats, Inbred SHR; Receptors, Angiotensin - metabolism; Signal Transduction; Hypertension; Heart failure; Prognosis; Rat; Enzyme; Pathogenesis; hypertrophy; signal transduction; Rodentia; Mitogen-activated protein kinase; Cardiovascular disease; Vertebrata; Mammalia; Heart disease; Animal; hypertension, genetic; G proteins; G protein
• ISSN: 0194-911X; 1524-4563
• DOI: 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 (AT1R) increased in left ventricular hypertrophy (LVH) and reverted to normal in CHF, whereas there was a downregulation of the Ang II type 2 receptor (AT2R) in CHF. At the transducer level, Gαq and Gα12 protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, Gβ and Gα13 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.