Lp-PLA(2) Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages

Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6C(high) and reparative Ly-6C(low) monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a member of the phospholipase A(2) family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA(2) levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA(2) in healing after MI. METHODS AND RESULTS—: In response to MI, Lp-PLA(2) levels markedly increased in the circulation. To test the functional importance of Lp-PLA(2), we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA(2)–deficient (bmLp-PLA(2)(−/−)). Compared with wild-type controls, bmLp-PLA(2)(−/−) mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA(2)(−/−) mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6C(high) monocytes. During the later, reparative phase, infarcts of bmLp-PLA(2)(−/−) mice contained Ly-6C(low) macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA(2)(−/−) mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction. CONCLUSIONS—: Lp-PLA(2) augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI.