LAUSR

Introduction and Hypothesis: Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. The innate immune response plays a major role in cardiac remodeling after AMI. Lysophosphatidic acid (LPA), produced by autotaxin (ATX) and degraded by Lipid phosphate phosphatase 3 (LPP3), regulates monocytosis and promotes inflammation. However, the role of LPP3 in post-AMI inflammation is not understood. Here, we investigated the possible role of Myeloid-specific Plpp3 KO mice in cardiac and systemic inflammation and resulting in adverse cardiac remodeling post-MI. Methods and Results: To generate mice with Myeloid-specific Plpp3 deletion , female Plpp3 fl/fl mice were crossed to male Plpp3 mice expressing Cre recombinase under the control of the LysM promoter to generate lysm-plpp3. mice. These mice and their littermate control underwent MI or sham surgery. Inflammatory cell content was assessed using flow cytometry and immunohistochemistry. Cardiac function and scar size were assessed by echocardiography and Mason Trichrome staining, respectively. Increased number of Ly6C hi monocytes (CD45 + /Ly6C/G hi /CD115 hi ) and pro-inflammatory macrophages (CD45 + /F4-80 + /CD11b + ) (CD45 + /F4-80 + /CD86 + ), in cardiac tissue of Cre+LysM mice was observed compared to Cre-fl/fl littermate controls during peak post-MI inflammation, as assessed by flow cytometry ( Fig.1A-C ). This increase in inflammatory cells and inflammation may be the consequence of the significant increase in bone marrow and spleen progenitor cell count and proliferation. Moreover, Cre+LysM mice cardiac functional recovery was also reduced significantly ( Fig. 1D-F ) as assessed by echocardiography. Conclusion: Myeloid-specific Plpp3 deletion increases the deleterious effects of inflammation on the ischemic myocardium and ATX/ LPA signaling could represent a novel therapeutic target for future clinical studies of coronary heart diseases.