Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction

项目总结/文摘

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.