title: Alterations of signal transduction system in heart failure.
abstract: Congestive heart failure (CHF) patients share several similar features, such as reduced cardiac contractility and neurohumoral activation to compensate the impaired cardiac function. In CHF patients, the cardiac renin-angitensin (RA) system, receptors, GTP-binding proteins, and their effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and the post-receptor signal transducing pathway. Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients and animal models. Although direct evidence for a change in catalytic protein of adenylyl cyclase has not been found, limited information has suggested a reduced catalytic activity in terminally failing hearts. In this paper, we have assessed the changes in beta AR, GTP-binding protein, catalytic protein and beta ARK. We also examined angiotensinogen mRNA expression in failing heart. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies revealed a stronger reaction in the endocardial layer of the human left ventricle than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT1 receptor RNA are present in ventricular muscles. Renin and Ao mRNA could not be detected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data indicate that the cardiac RA system plays an important role in the deterioration of cardiac function.
authors.affiliation: Department of Laboratory Medicine and Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: A
authors.initials: A
authors.lastname: Kitabatake
mesh_terms: D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D000808:Angiotensinogen; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D019204:GTP-Binding Proteins