Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction

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 numbers of 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 the majority of research focuses on monocyte production following AMI, the mechanism(s) of monocyte egress from the spleen and early cardiac infiltration after AMI are poorly understood. We have recently demonstrated the role of bioactive lipids in the mobilization of BMCs following AMI. LPA, a signaling bioactive lipid, plays an important role in activating inflammatory monocytes, regulating their peripheral blood count and homing them to sites of inflammation. Our preliminary studies indicate that LPA levels are elevated early in PB and cardiac tissues after AMI in humans and mice. We hypothesize that LPA acts systemically to enhance monocyte egress from the BM and spleen and locally; through its chemoattractant, cytokine production and endothelial barrier effects; to facilitates their cardiac infiltration. Our long-term research goal is to contribute toward the development of new clinically useful therapies for AMI injury. The overall objective for this application is to define LPA mediated signaling pathways linking AMI to the inflammatory BM response. The rationale for the proposed research is that its completion is expected to offer new approaches to reduce inflammation and improve cardiac recovery after AMI. The central hypothesis is that LPA plays an important role in initiating and maintaining the inflammatory response thus impairing cardiac recovery after AMI. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the molecular mechanism(s) that control LPA production after acute myocardial infarction, 2) Examine the regulatory mechanisms of the ATX/LPA axis in monocytosis after acute myocardial infarction, and 3) Determine the local effect of LPA on cardiac endothelial cells after myocardial infarction. Results of these studies are expected to define new mechanistic understanding of AMI-induced ATX/LPA signaling, their contribution to AMI-associated systemic monocytosis and cardiac inflammation and the role of endothelial ATX/LPA signaling in monocyte recruitment to the injured myocardium. To attain this goal, we will combine human studies with animal models with genetic manipulation of key components of the ATX/LPA signaling. Our 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 our innovative focus on the ATX/LPA signaling nexus as a critical mechanism in the early phase of AMI-induced cardiac inflammation and the potential to control post-AMI infarct expansion by dampening the pathological inflammatory response and subsequent development of heart failure.