Project Abstract: Manikandan Panchatcharam, PhD

“Oxidative Stress Mediated Myocardial Lipid Dysfunction”

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 Tcells) 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.

The Center for Redox Biology and Cardiovascular Disease is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121307.