Cell responsiveness to hormone and neurotransmitter stimulation is dependent upon elements in signal transduction pathways. The quantity and interactions of these elements (receptor.transducer.effector) ultimately determines the physiological impact of receptor activation. The cardiac myocyte, whose rate and force of contraction are driven by adrenergic stimulation via the beta-adrenergic receptor.G.protein.adenylyl cyclase system, provides an excellent means for detailed analyses of signal transduction. What remain almost totally unexplored are the molecular mechanisms underlying these changes. This is the goal of the current proposal. By combining biochemical and molecular studies with physiological examination of altered expression of the betaAR pathway in vivo, the molecular mechanisms responsible for altered myocardial adrenergic function will be elucidated. Two animal models of pathophysiological entities which comprise a major proportion of cardiovascular morbidity and mortality will be studied: myocardial ischemia, and congestive heart failure (CHF). First, the changes in myocardial betaAR-expression and G-protein function in the setting of experimentally induced CHF will be delineated, and then the molecular mechanisms important in the development of these changes will be determined. Then the effects of chronic ischemia on myocardial adrenergic function will be examined. The studies proposed for the ischemia model have never before been performed; furthermore, the approaches proposed for the congestive heart failure model are new. The application of biochemical, cell biological, and molecular biological approaches to animal models of clinically relevant disorders is likely to yield important new mechanistic information. To obtain a greater understanding of the molecular pathophysiology of these prevalent clinical disorders is a primary goal of this proposal.
