Alcohol mediated myocardial lysophosphatidic acid signaling

摘要 长期长期酗酒会导致心肌功能障碍，导致心力衰竭。这个 酒精导致心脏损伤的机制尚不清楚。线粒体功能障碍起到了 细胞改变在酒精性心肌病发生和并发症中的重要作用 血脂水平。在细胞培养模型中，溶血磷脂酸(LPA)信号的升高诱导了 心肌细胞功能障碍(增强的心钠素[ANP]和脑钠素[BNP] 表达)。溶血磷脂酸的产生涉及到分泌物对溶血磷脂酰胆碱的水解 酶自体趋化蛋白，而磷脂磷酸酶-3(LPP3)催化溶血磷脂酸 去磷酸化以产生不具有受体活性的脂类产物。在此应用程序中，我们呈现 首次有证据表明，大量饮酒提高了心肌自体趋化素水平，降低了LPP3 表达，这与溶血磷脂酸信号的增加有关。我们推测 酗酒，氧化还原敏感的转录因子NFAT(活化T细胞的核因子) 与自体趋化蛋白启动子结合并诱导其表达。此外，酒精会反式激活microRNA-92a， 它是LPP3的负调控因子。因此，我们假设大量饮酒会改变自体分类。 和LPP3的表达驱动溶血磷脂酸信号转导和心肌功能障碍。以下是 相互关联的特定目标旨在提供体外、体内和体内的逐步和深入的研究。 实验治疗学环境。特定目标1将评估酒精诱导的自体趋化蛋白表达的作用 以及心肌中溶血磷脂酸的产生。具体目标2将决定酒精的作用- 介导心肌LPP3耗竭和溶血磷脂酸调节。我们可以确定是否 细胞外和细胞内抗氧化状态的调节赋予了不同的保护作用 暴露在酗酒的环境中。这项研究不仅将扩大我们对酒精的理解-- 自体趋化因子-LPA-LPP3介导了心力衰竭，但也将为未来的临床干预确定新的靶点。

Abstract Chronic long-term abuse of alcohol leads to myocardial dysfunction and results in heart failure. The mechanism by which alcohol causes cardiac damage remains unclear. Mitochondrial dysfunction plays a significant role in the development and complications of alcoholic cardiomyopathy due to changes in cellular lipid levels. In cell culture models, elevated lysophosphatidic acid (LPA) signaling induces markers of cardiomyocyte dysfunction (enhanced Atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP] expression). 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 enhances the myocardial autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. We speculate that upon heavy alcohol consumption, the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) bind to the autotaxin promoter and induce its expression. Furthermore, alcohol transactivates microRNA-92a, which is a negative regulator of LPP3. Thus, we hypothesize that heavy alcohol consumption alters autotaxin and LPP3 expression to drive lysophosphatidic acid signaling and myocardial 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 alcohol-induced autotaxin expression and lysophosphatidic acid production in the myocardium. Specific Aim 2 will determine the role of alcohol- mediated LPP3 depletion and lysophosphatidic acid regulation in the myocardium. We could identify whether modulation of extracellular versus intracellular antioxidant status confers a differential protective effect upon exposure to heavy alcohol consumption. This study will not only extend our understanding of alcohol- autotaxin-LPA-LPP3 mediated cardiac failure but will also identify novel targets for future clinical interventions.