Prostaglandins are potent modulators of numerous physiologic and pathophysiologic processes. Preliminary studies indicate that some prostaglandins, including PGE2, P6F1alpha and PGF2alpha stimulate growth of neonatal rat heart myocytes in culture, while other prostaglandins, P6E1 and PGI2, do not. The ability of the heart to increase its size and pumping capacity in response to a chronically heightened hemodynamic load is essential for maintaining oxygen delivery and sustaining life. Abnormal cardiac enlargement, however, may portend coronary disease, congestive heart failure, and stroke. Myocardial infarction and sustained dynamic exercise, conditions which increase the work load on the heart and often result in cardiac hypertrophy, are associated with an elevated prostaglandin efflux from cardiac tissue. Furthermore, a strong association exists between skeletal muscle protein synthesis and prostaglandins. The broad, long-term objectives of this proposal is to examine the effects of natural prostaglandins on cardiac myocyte growth/hypertrophy and to uncover the intracellular means by which prostaglandins regulate growth/hypertrophy of the heart. Accordingly, the specific aims are: I. To characterize the effects of prostaglandins on growth/hypertrophy of cultured neonatal rat cardiac myocytes by observing changes in cell morphology, protein turnover and accumulation, DNA synthesis and cell number, levels of specific proteins and mRNAs, and transcriptional activation of transfected genes. II. To ascertain whether and to what extent, treatments known to modulate cardiac growth in vivo and in vitro mediate their effects on cultured cardiac muscle cells via prostaglandins by investigating inhibition of growth/hypertrophy induced by stretch, alpha1-adrenergic stimulation, angiotensin II, or endothelin-1 with prostaglandin synthesis inhibitors, measuring prostaglandin efflux from stimulated cells, determining if myocytes are responsible for the prostaglandin efflux of stimulated cells, and measuring changes in the level of expression of prostaglandin synthesis genes. III. To determine the general intracellular signalling pathways by which prostaglandins act by assessing the involvement inositol phosphates, cAMP, and protein kinases A and C in the prostaglandin-induced growth response. Results from these experiments should foster future study of the role of prostaglandins in the regulation of cardiac myocyte growth.
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