Lysophospholipids and gelsolin in cardioprotection

描述(由申请人提供)： 该项目建议检查心肌保护、损伤和修复的两个方面，这两个方面以前没有在心脏中进行过研究： 第一个目标是确定溶血磷脂1-磷酸鞘氨醇(S1P)和溶血磷脂酸(LPA)保护心脏免受缺血/再灌流和缺氧/复氧等干预措施所产生的急性氧化应激的机制。S1P和LPA与G蛋白偶联受体家族(内皮分化基因或EDG受体)结合，引起多种细胞反应。其中最突出的是对细胞死亡的保护。我们假设S1P和LPA通过传递涉及一种或多种蛋白激酶C(PKC)，特别是epsilon PKC的信号来发挥心脏保护作用。此外，还将研究由Gi、PI-3激酶、Akt及其下游效应器介导的替代信号。我们还将测试这一假设，即这些心脏保护信号转导机制的末端效应器最终驻留在线粒体中，特别是复合体I。这些研究将广泛使用一种基因工程小鼠模型，即epsilon PKC缺失小鼠。 第二个目标是了解与LPA结合的肌动蛋白调节蛋白明胶蛋白在心肌损伤的急性和长期反应中的作用。这些实验将利用第二种基因工程小鼠模型，即明胶蛋白缺失小鼠。我们假设这只小鼠将非常容易受到急性心肌缺血和梗塞的影响。由于明胶蛋白是线粒体功能的关键调节因子，我们预计明胶蛋白缺失的小鼠将在线粒体跨膜电位、呼吸活性和复合体i活性方面表现出严重的异常。我们还预计，该小鼠模型在实验性心肌梗死后将表现出适应性不良的左心室重构和过度纤维化。我们假设，这些异常中的许多可以通过给予细胞松弛素D等药物来逆转或预防，细胞松弛素D是一种解聚肌动蛋白细丝的真菌毒素。

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.