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 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 (3µg/kg/day) was injected 3 hr 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 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.

MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury

“…Although not addressed in this study, MerTK activation also leads to the production of 12,15-LOX-derived specialized proresolving mediators/SPMs 8 . Our unpublished findings after ELISA support a MerTK-SPM axis in the heart, however, assays of higher specificity, such as LC-MS/MS, are required for confirmation 40, 41 . Thus, an additional benefit of protecting MerTK from I/R associated cleavage is likely through its anti-inflammatory and pro-resolving function.…”

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

“…The 12/15LOX -/- spleen exhibited an increase in F4/80 + /CD206 + macrophages with an elevated mRNA levels of Ym-1 . Our previous study indicates that the splenic proresolving lipid mediator RvD1 contributes to the resolution of inflammation [33]. Metabololipidomic analysis suggested an increase in CYP-derived EETs, termed as C epoxins, with an increase in CYP2J expression in 12/15LOX -/- mouse spleens.…”

n-3 Fatty acid supplementation and proresolving mediators of inflammation

“…The actions of SPMs in animal models of disease have been extensively reviewed [4 && ] and include controlling inflammatory pain (RvE1, RvD1, 17R-RvD1, RvD2, and Mar1), accelerating wound healing in diabetes (RvD1), inhibiting secondary thrombosis and necrosis in burn injury (RvD2), preventing colitis (RvE1, RvD1, and RvD2), protection against reperfusion injury in the heart (RvE1), and inhibiting kidney fibrosis (RvE1 and RvD1). Recent studies also indicate that RvE1 given orally to rabbits attenuated atherosclerosis induced by diet or periodontitis [15], and RvD1 injected subcutaneously to mice improved ventricular function following myocardial infarction [16]. The precursors to the E and D-series resolvins, 18-HEPE and 17-HDHA, are also biologically active.…”