title: 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: Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA.
authors: Vasundhara
authors: V
authors: Kain
authors: Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA.
authors: Kevin A
authors: KA
authors: Ingle
authors: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, MA USA.
authors: Romain A
authors: RA
authors: Colas
authors: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, MA USA.
authors: Jesmond
authors: J
authors: Dalli
authors: Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA.
authors: Sumanth D
authors: SD
authors: Prabhu
authors: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, MA USA.
authors: Charles N
authors: CN
authors: Serhan
authors: Chicago College of Pharmacy, Department of Pharmaceutical Sciences, Midwestern University, IL, USA.
authors: Medha
authors: M
authors: Joshi
authors: Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA. Electronic address: halade@uab.edu.
authors: Ganesh V
authors: GV
authors: Halade
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D002452:Cell Count; D016764:Cell Polarity / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000187:drug effects / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011654:Pulmonary Edema / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology*; D014463:Ultrasonography; D016276:Ventricular Function / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D003094:Collagen; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases
keywords: Metabololipidomics; Myocardial infarction; Neutrophils; Resolution of inflammation; Resolvin D1; Splenic remodeling