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

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.

• Authors: Vasundhara Kain, Kevin A Ingle, Romain A Colas, Jesmond Dalli, Sumanth D Prabhu, Charles N Serhan, Medha Joshi, Ganesh V Halade
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 84 Pg. 24-35 (Jul 2015) ISSN: 1095-8584 [Electronic] England
• PMID: 25870158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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