Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function

J Mol Cell Cardiol. 2015 Jul;84:24-35. doi: 10.1016/j.yjmcc.2015.04.003. Epub 2015 Apr 11.

Abstract

Unresolved inflammation is a major contributor to the development of heart failure following myocardial infarction (MI). Pro-resolving lipid mediators, such as resolvins (e.g. RvD1), are biosynthesized endogenously. The role of RvD1 in resolving post-MI inflammation has not been elucidated due to its unstable nature. Here, we have tested the role for two forms of RvD1, after incorporation into liposomes (Lipo-RvD1) and its free acid form (RvD1) in the left ventricle (LV) and splenic remodeling post-MI. 8 to 12-week old male, C57BL/6J-mice were subjected to coronary artery ligation and Lipo-RvD1 or RvD1 (3 μg/kg/day) was injected 3h post-MI for day (d)1 or until d5. No-MI mice and saline-injected MI mice served as controls. RvD1 injected groups showed improved fractional shortening post-MI; preserving transient changes in the splenic reservoir compared to MI-saline. RvD1-groups showed an early exit of neutrophils from LV and spleen at d5 post-MI with an increased expression of lipoxin A4 receptor (ALX; synonym formyl peptide receptor; FPR2) compared to the MI-saline group. The levels of pro-resolving mediators RvD1, RvD2, Maresin 1 (MaR1) and Lipoxin A4 (LXA4) were increased in spleens from RvD1 injected mice at d5 post-MI. RvD1 administration reduced macrophage density, ccr5 and cxcl5 levels at d5 post-MI compared to saline injected mice (both, p < 0.05). Increased transcripts of mrc-1, arg-1 and Ym-1 (all, p < 0.05) suggest macrophage-mediated clearance of necrotic cells in RvD1-groups. RvD1 reduced the pro-fibrotic genes (colla1, coll2a1 and tnc (all; p < 0.05)) and decreased collagen deposition, thereby reducing post-MI fibrosis and thus stabilizing the extracellular matrix. In summary, RvD1 and Lipo-RvD1 promote the resolution of acute inflammation initiated by MI, thereby delaying the onset of heart failure.

Keywords: Metabololipidomics; Myocardial infarction; Neutrophils; Resolution of inflammation; Resolvin D1; Splenic remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / metabolism
  • Cardiomegaly / complications
  • Cardiomegaly / diagnostic imaging
  • Cardiomegaly / drug therapy
  • Cardiomegaly / physiopathology
  • Cell Count
  • Cell Polarity / drug effects
  • Collagen / metabolism
  • Docosahexaenoic Acids / chemistry
  • Docosahexaenoic Acids / pharmacology
  • Docosahexaenoic Acids / therapeutic use*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / genetics
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology*
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Myocardial Infarction / complications
  • Myocardial Infarction / diagnostic imaging
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / physiopathology*
  • Neutrophil Infiltration / drug effects
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Pulmonary Edema / complications
  • Pulmonary Edema / drug therapy
  • Pulmonary Edema / physiopathology
  • Receptors, Formyl Peptide / metabolism
  • Spleen / drug effects
  • Spleen / pathology*
  • Ultrasonography
  • Ventricular Function / drug effects*
  • Ventricular Remodeling / drug effects

Substances

  • Receptors, Formyl Peptide
  • formyl peptide receptor 2, mouse
  • resolvin D1
  • Docosahexaenoic Acids
  • Collagen
  • Arachidonate 5-Lipoxygenase
  • Prostaglandin-Endoperoxide Synthases