guanosine-triphosphate and Cardiomegaly

Topics: Animals; Calcium; Cardiomegaly; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Protein Glutamine gamma Glutamyltransferase 2; Signal Transduction; Thromboxanes; Transglutaminases

Small guanine nucleotide-binding proteins of the Ras and Rho (Rac, Cdc42, and Rho) families have been implicated in cardiac myocyte hypertrophy, and this may involve the extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and/or p38 mitogen-activated protein kinase (MAPK) cascades. In other systems, Rac and Cdc42 have been particularly implicated in the activation of JNKs and p38-MAPKs. We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes. Endothelin 1 and phenylephrine (both hypertrophic agonists) induced rapid activation of endogenous Rac1, and endothelin 1 also promoted significant activation of RhoA. Toxin B (which inactivates Rho family proteins) attenuated the activation of JNKs by hyperosmotic shock or endothelin 1 but had no effect on p38-MAPK activation. Toxin B also inhibited the activation of the ERK cascade by these stimuli. In transfection experiments, dominant-negative N17Rac1 inhibited activation of ERK by endothelin 1, whereas activated V12Rac1 cooperated with c-Raf to activate ERK. Rac1 may stimulate the ERK cascade either by promoting the phosphorylation of c-Raf or by increasing MEK1 and/or -2 association with c-Raf to facilitate MEK1 and/or -2 activation. In cardiac myocytes, toxin B attenuated c-Raf(Ser-338) phosphorylation (50 to 70% inhibition), but this had no effect on c-Raf activity. However, toxin B decreased both the association of MEK1 and/or -2 with c-Raf and c-Raf-associated ERK-activating activity. V12Rac1 cooperated with c-Raf to increase expression of atrial natriuretic factor (ANF), whereas N17Rac1 inhibited endothelin 1-stimulated ANF expression, indicating that the synergy between Rac1 and c-Raf is potentially physiologically important. We conclude that activation of Rac1 by hypertrophic stimuli contributes to the hypertrophic response by modulating the ERK and/or possibly the JNK (but not the p38-MAPK) cascades.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cells, Cultured; Endothelin-1; Enzyme Activation; Gene Expression Regulation; Guanosine Triphosphate; Humans; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinases; Myocardium; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-raf; rac1 GTP-Binding Protein; Rats; rhoA GTP-Binding Protein; Transfection

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Cardiomegaly; Catecholamines; Guanosine Triphosphate; Heart; Myocardium; Rats; Receptors, Adrenergic, beta; Sympathetic Nervous System

The cytosol fraction of rat heart contains an initiation factor-like protein component that behaves like the eukaryotic factor (eIF-2) in binding [35S]-Met-tRNAf in the presence of GTP. The ternary initiator complex thus formed is able to bind to heart ribosomes. In the left ventricle of rat heart undergoing hypertrophic growth upon constriction of the descending aorta, the [35S]-Met-tRNAf binding activity of the cytosol protein(s) gradually increases after the operation from 40%, at 48 h, to 90%, at 10 days; slightly lower activation is seen in the [35S]-Met-tRNAf binding to ribosomes. Polysomal RNA is extracted from sham operated and hypertrophic rat hearts and translated in a reticulocyte cell free system. The translation products are analyzed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis: no clearcut qualitative difference is observed in the pattern obtained from sham operated and hypertrophic animals.

Topics: Animals; Cardiomegaly; Cell-Free System; Cytosol; Electrophoresis, Polyacrylamide Gel; Guanosine Triphosphate; In Vitro Techniques; Male; Myocardium; Peptide Chain Initiation, Translational; Protein Biosynthesis; Rats; Rats, Inbred Strains; Ribosomal Proteins; Ribosomes; RNA, Ribosomal; RNA, Transfer, Amino Acyl; RNA, Transfer, Met; Sulfur Radioisotopes

Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.

Topics: Adenine Nucleotides; Cardiomegaly; Coronary Disease; Guanosine Triphosphate; Humans; Myocardium; NAD; Nucleotides; Phosphocreatine; Pyrimidine Nucleotides