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

Shun He, Benjamin G. Chousterman, Ashley Fenn, Atsushi Anzai, Manfred Nairz, Martin Brandt, Ingo Hilgendorf, Yuan Sun, Yu Xiang Ye, Yoshiko Iwamoto, Benoit Tricot, Ralph Weissleder, Colin MacPhee, Peter Libby, Matthias Nahrendorf, Filip K. Swirski

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4 Citations (Scopus)

Abstract

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-α, interleukin (IL)-1β, 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.

Original languageEnglish
Pages (from-to)980-987
Number of pages8
JournalCirculation: Heart Failure
Volume8
Issue number5
DOIs
Publication statusPublished - 2015 Sep 1

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Keywords

  • Heart failure
  • inflammation
  • macrophages
  • monocytes
  • myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

He, S., Chousterman, B. G., Fenn, A., Anzai, A., Nairz, M., Brandt, M., Hilgendorf, I., Sun, Y., Ye, Y. X., Iwamoto, Y., Tricot, B., Weissleder, R., MacPhee, C., Libby, P., Nahrendorf, M., & Swirski, F. K. (2015). Lp-PLA2 Antagonizes Left Ventricular Healing after Myocardial Infarction by Impairing the Appearance of Reparative Macrophages. Circulation: Heart Failure, 8(5), 980-987. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002334