Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages

Background—Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6Chigh and reparative Ly-6Clow 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 A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 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-PLA2 in healing after MI. Methods and Results—In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA2–deficient (bmLp-PLA2−/−). Compared with wild-type controls, bmLp-PLA2−/− mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-&agr;, interleukin (IL)-1&bgr;, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2−/− mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6Chigh monocytes. During the later, reparative phase, infarcts of bmLp-PLA2−/− mice contained Ly-6Clow 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-PLA2−/− mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction. Conclusions—Lp-PLA2 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.

[1]  Solid-Timi Investigators.  Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. , 2014 .

[2]  P. Libby,et al.  Chigh Monocytes Depend on Nr 4 a 1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium , 2014 .

[3]  Xiaofei Qin,et al.  Lysophosphatidylcholine perpetuates macrophage polarization toward classically activated phenotype in inflammation. , 2014, Cellular immunology.

[4]  P. Pais,et al.  Darapladib for preventing ischemic events in stable coronary heart disease. , 2014, The New England journal of medicine.

[5]  A. A. Kapralov,et al.  Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2 , 2014, Cell Death and Differentiation.

[6]  Daniel G. Anderson,et al.  In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. , 2013, Journal of the American College of Cardiology.

[7]  Dylan L. Steen,et al.  Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. , 2014, JAMA.

[8]  M. Nahrendorf,et al.  Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure , 2013, Science.

[9]  S. Sheardown,et al.  The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in aspergillus fumigatus sensitized mice , 2012, Respiratory Research.

[10]  A. Feigl,et al.  The Global Economic Burden of Noncommunicable Diseases , 2012 .

[11]  E. Braunwald,et al.  Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. , 2011, American heart journal.

[12]  C. Held,et al.  Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. , 2010, American heart journal.

[13]  P. Libby,et al.  Impaired infarct healing in atherosclerotic mice with Ly-6C(hi) monocytosis. , 2010, Journal of the American College of Cardiology.

[14]  F. Meyer,et al.  Expression of lipoprotein-associated phospholipase A(2) in carotid artery plaques predicts long-term cardiac outcome. , 2009, European heart journal.

[15]  T. Akasaka,et al.  Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. , 2009, Journal of the American College of Cardiology.

[16]  Ping Zhang,et al.  Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development , 2008, Nature Medicine.

[17]  Frits Mastik,et al.  Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque , 2008, Circulation.

[18]  P. Libby,et al.  The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions , 2007, The Journal of experimental medicine.

[19]  S. Tsimikas,et al.  In Atherosclerosis and Cardiovascular Disease 2 Phospholipase a New Insights into the Role of Lipoprotein(a)-associated Lipoprotein-associated , 2022 .

[20]  R. Wilensky,et al.  Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. , 2007, Atherosclerosis.

[21]  R. Virmani,et al.  Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary Atherosclerosis , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[22]  A. Jaffe,et al.  Lipoprotein-Associated Phospholipase A2 and Prognosis After Myocardial Infarction in the Community , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[23]  A. Zalewski,et al.  Role of Lipoprotein-Associated Phospholipase A2 in Atherosclerosis: Biology, Epidemiology, and Possible Therapeutic Target , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[24]  A. Hofman,et al.  Lipoprotein-Associated Phospholipase A2 Activity Is Associated With Risk of Coronary Heart Disease and Ischemic Stroke: The Rotterdam Study , 2005, Circulation.

[25]  Hung‐Yuan Cheng,et al.  The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man. , 2002, Bioorganic & medicinal chemistry letters.

[26]  K. Eagle,et al.  Excess mortality of type A aortic dissection in women: impact of delayed diagnosis , 2002 .

[27]  S. Ishikawa,et al.  Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling. , 2002, Journal of the American College of Cardiology.

[28]  T. Häkkinen,et al.  Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[29]  D. Tew,et al.  Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. , 1999, The Biochemical journal.

[30]  C. Southan,et al.  Purification, properties, sequencing, and cloning of a lipoprotein-associated, serine-dependent phospholipase involved in the oxidative modification of low-density lipoproteins. , 1996, Arteriosclerosis, thrombosis, and vascular biology.