Lysophospholipids and gelsolin in cardioprotection

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DESCRIPTION (provided by applicant): This project proposes to examine two aspects of myocardial protection, injury, and repair that have not previously been studied in the heart: The first goal is to identify the mechanisms by which the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) protect the heart against acute oxidative stress produced by interventions such as ischemia/reperfuson and hypoxia/reoxygenation. S1P and LPA bind to a family of G-protein-coupled receptors (endothelial differentiation gene or Edg receptors) and evoke a variety of cellular responses. Prominent among these is protection against cell death. We hypothesize that S1P and LPA exert cardioprotective effects by transducing signals involving one or more isoforms of protein kinase C (PKC), particularly epsilon PKC. Alternative signals mediated by Gi, PI-3 kinase, Akt, and their downstream effectors will also be studied. We also will test the hypothesis that the end-effectors of these cardioprotective signal transduction mechanisms ultimately reside in the mitochondria, especially Complex I. These studies will make extensive use of a genetically engineered mouse model, the epsilon PKC null mouse. The second goal is to understand the role of the actin-regulatory protein gelsolin, which binds to LPA, in the acute and long-term responses to myocardial injury. These experiments will utilize a second genetically engineered mouse model, the gelsolin null mouse. We hypothesize that this mouse will be highly vulnerable to acute myocardial ischemia and infarction. As gelsolin is a key regulator of mitochondrial function, we expect that the gelsolin null mouse will exhibit profound abnormalities in mitochondrial transmembrane potential, respiratory activity, and Complex I activity. We also expect that this mouse model will exhibit maladaptive left ventricular remodeling and excessive fibrosis after experimental myocardial infarction. We hypothesize that many of these abnormalities can be reversed or prevented by administration of agents such as cytochalasin D, a fungal toxin that depolymerizes actin filaments.