Alcohol-LPP3 axis in ischemic stroke

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Project Abstract Complications of alcoholism such as stroke and cardiomyopathy are leading causes of death among adults. The underlying pathophysiology of these events involves lipids within susceptible arteries leading to subsequent localized inflammation and vascular dysfunction. While the bioactive glycerophospholipid lysophosphatidic acid plays a well-known role in atherosclerotic disease, its role in alcohol-mediated cerebral dysfunction remains virtually unexplored. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption (HAC) enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. Upon HAC, reactive oxygen species (ROS) increases in the cerebrovasculature, whereas 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 HAC through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that HAC alters autotaxin and LPP3 expression through ROS production to drive lysophosphatidic acid signaling and cerebrovascular 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 ROS production in autotaxin expression and lysophosphatidic acid production in the cerebrovasculature following HAC. Specific aim 2 will determine the role of ROS production in LPP3 depletion and LPA production in the cerebrovasculature following HAC. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect following HAC. Our results should provide specific insight into signaling systems mediated by HAC and may provide novel targets for treatment and might improve cerebrovascular disorders.