Acute myocardial infarction and resulting ischemic heart disease are the single most prevalent cause of morbidity and mortality in the western world. While the bioactive glycerophospholipid lysophosphatidic acid (LPA) plays a well-known role in atherosclerotic disease, its role in myocardial function remains virtually unexplored. Following acute myocardial infarction, serum LPA concentration rises by six-fold over control subjects, suggesting LPA may contribute to the pathogenesis of myocardial infarction. LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes LPA dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that cardiac ischemia/reperfusion (I/R) injury enhances myocardial autotaxin levels and decreases myocardial LPP3 expression, and this is associated with increased serum LPA levels. Upon reperfusion, reactive oxygen species production arises as a burst of superoxide from mitochondria following I/R injury. The redox-sensitive transcription factor NFAT (a nuclear factor of activated T- cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of I/R injury through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that I/R injury alters autotaxin and LPP3 expression through mitochondrial superoxide production to drive LPA signaling and cardiomyocyte dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings.
Specific aim 1 will assess the role of myocardial superoxide production in autotaxin expression and LPA production in I/R injury metabolism.
Specific aim 2 will determine the role of mitochondrial superoxide production in LPP3 depletion and LPA production in I/R injury. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect in I/R injury models.
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