ALTERATIONS OF SIGNAL-TRANSDUCTION SYSTEM IN HEART-FAILURE

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 cardia c renin-angitensin (RA) system, receptors, GTP-binding proteins, and t heir effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chron ic 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 protei n (Gi) can be increased in CHF patients and animal models. Although di rect evidence for a change in catalytic protein of adenylyl cyclase ha s not been found, limited information has suggested a reduced catalyti c activity in terminally failing hearts. In this paper, we have assess ed 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 atr ial 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 ventricl e than in the epicardial layer, and intense immunoreactivity in the co nduction system and right atrium. Our experiments revealed a widesprea d immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT(1) receptor RN A are present in Ventricular muscles. Renin and Ao mRNA could not be d etected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data ind icate that the cardiac RA system plays an important role in the deteri oration of cardiac function.