REGULATION OF CARDIAC CONTRACTILITY BY DIACYLGLYCEROL

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Abstract. The broad, long-term objectives of the proposed research are to elucidate mechanisms underlying the regulation of myocardial contraction by diacylglycerol and protein kinase C. Many extracellular chemical signals such as hormones, neurotransmitters, cytokines, growth factors, mechanical stress and oxygen stress may regulate cardiac contractility by mobilizing lipid second messengers including diacylglycerol and cis- unsaturated fatty acids. There are at least four enzyme systems, PLA2, PLC-beta, PLC-gamma and PLD involved in generating these lipid messengers giving rise to a potentially information-rich signal encoded in lipid species generating these lipid messengers giving rise to a potentially information-rich signal encoded in lipid species, timing and location in a systematic way in order to establish the influence of these parameters on contractile regulation. cis-Unsaturated fatty acids and Ca will be investigated as putative co-messengers with diacylglycerol that may selectively activate protein kinase C isoforms alpha, epsilon or delta. The mechanisms of protein kinase C anchoring to sites on the transverse tubules and to sites on the myofilament will be examined and their respective roles in regulating systolic Ca levels and myofilament Ca sensitivity will be established. Whether protein kinase C mediated phosphorylation of cardiac troponin I is a major mechanism underlying positive or negative inotropic responses in ventricular myocytes will also be established. The goal is to use a combination of modern and innovative methodologies in cell biophysics, imaging and molecular biology to provide unambiguous answers to fundamental questions about diacylglycerol signaling in the heart. This research will further our understanding of basic mechanisms by which lipid messengers alter cardiac physiology, and mechanisms of protein kinase C regulation of cardiac troponin I function, so that defects in these pathways in various diseased states can be identified and corrected. The proposed research will be highly interactive with other subprojects and will rely to a significant extent on the expertise of other investigators in the Program. Overall, this research addresses a major theme of the Program involving elucidation of signal transduction mechanisms evoked by membrane receptor antagonists in myocardium.