Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction

项目总结/摘要 缺血性心脏病是美国人群发病率和死亡率的主要原因， 急性心肌梗死（AMI）。AMI引发炎症反应，导致循环增加 炎性骨髓细胞（BMC），特别是单核细胞（单核细胞增多症）。这种反应对于 移除坏死组织并启动愈合过程然而， AMI可能是有害的，并且与梗死扩展、不良心脏重塑和不良临床表现相关。 结果。虽然大多数研究集中在AMI后单核细胞的产生，但单核细胞的产生机制还不清楚。 对AMI后从骨髓的排出和早期心脏浸润了解甚少。我们的初步数据 证明了信号生物活性脂质溶血磷脂酸（LPA）在AMI后动员中的作用， BMC。由自分泌运动因子（ATX）产生的LPA在激活炎性单核细胞中起关键作用， 调节它们的外周血细胞计数并将它们引导到炎症部位。初步研究还 表明，在人和小鼠中，AMI后PB和心脏组织中的LPA水平早期升高。很长的- 长期目标是为AMI损伤的新的临床有用的疗法的发展做出贡献。总体目标 本申请的目的是定义LPA介导的连接AMI与炎性BM反应的信号传导途径。 这项研究的基本原理是它有可能提供新的方法来减少炎症， 改善AMI后心脏恢复。核心假设是LPA在启动和 维持AMI后炎症反应，从而损害心脏恢复。这一假设将得到检验 通过追求三个具体的目标：1）确定导致血浆LPA升高的分子机制， AMI，2）确定ATX/LPA轴促进AMI后单核细胞增多的信号传导系统，和3）定义 LPA水平、LPA受体1的遗传变异性（预测受体 表达和单核细胞增多。这些研究结果有望提供新的 对AMI诱导的ATX/LPA信号传导机制的理解，它们对AMI相关系统性 单核细胞增多症和心脏炎症以及遗传性基因突变在单核细胞增多症和 人类的炎症为了实现这一目标，拟议中的项目将把联合收割机人类研究与动物模型结合起来 通过对ATX/LPA信号传导的关键成分进行遗传操作。该小组在以下方面拥有丰富的经验： 研究AMI后心脏/BM信号传导以及ATX/LPA信号传导途径。这些因素的总体影响 研究源于对ATX/LPA信号联系的创新关注，ATX/LPA信号联系是AMI诱导艾德 炎症和潜在的控制后AMI梗死扩大和随后的心力衰竭， 这种病理反应。

PROJECT SUMMARY/ABSTRACT Ischemic heart disease is the leading cause of morbidity and mortality in the U.S. population and is often caused by acute myocardial infarction (AMI). AMI initiates an inflammatory response leading to increased circulating inflammatory bone marrow cells (BMCs), particularly monocytes (monocytosis). This response is crucial for removing dead tissue and initiating the healing process. However, exacerbated inflammatory response following AMI can be detrimental and is associated with infarct expansion, poor cardiac remodeling and adverse clinical outcomes. While most studies focus on monocyte production following AMI, the mechanism(s) of monocyte egress from the bone marrow and early cardiac infiltration after AMI are poorly understood. Our preliminary data demonstrate the role of the signaling bioactive lipid, lysophosphatidic acid (LPA), in the post-AMI mobilization of BMCs. LPA, produced by the enzyme autotaxin (ATX), plays a key role in activating inflammatory monocytes, regulating their peripheral blood count and homing them to sites of inflammation. Preliminary studies also indicated that LPA levels are elevated early in PB and cardiac tissues after AMI in humans and mice. The long- term goal is to contribute to development of new clinically useful therapies for AMI injury. The overall objective of this application is to define LPA mediated signaling pathways linking AMI to the inflammatory BM response. The rationale for the proposed research is its potential to offer new approaches to reduce inflammation and improve cardiac recovery after AMI. The central hypothesis is that LPA plays a key role in initiating and maintaining the post-AMI inflammatory response, thus impairing cardiac recovery. This hypothesis will be tested by pursuing three specific aims: 1) Identify the molecular mechanism(s) that result in elevated plasma LPA after AMI, 2) Determine the signaling systems by which ATX/LPA axis promotes monocytosis after AMI, and 3) define the association between LPA levels, heritable genetic variability in LPA receptor 1 that predicts receptor expression and monocytosis after AMI in humans. Results of these studies are expected to provide new mechanistic understanding of AMI-induced ATX/LPA signaling, their contribution to AMI-associated systemic monocytosis and cardiac inflammation and the role of heritable genetic mutations in monocytosis and inflammation in humans. To attain this goal, the proposed project will combine human studies with animal models with genetic manipulation of key components of the ATX/LPA signaling. This group has extensive experience in studying heart/BM signaling after AMI as well as ATX/LPA signaling pathways. The overall impact of these studies derives from an innovative focus on the ATX/LPA signaling nexus as a critical mechanism in AMI-induc ed inflammation and the potential to control post-AMI infarct expansion and subsequent heart failure by dampening this pathological response.