Abstract 12625: Splenic Leukocytes Defines the Resolution of Inflammation and Left Ventricle Healing in Heart Failure Pathology

Abstract

Introduction: After myocardial infarction (MI) self-healing is prominent in mice but not in humans. MI-induced innate inflammatory and resolving response is unclear in left ventricle (LV) healing. Hypothesis: To define innate and resolving response, our aim was to quantitate time-dependent generation of specialized pro-resolving mediators (SPMs) and leukocyte trafficking in the LV and spleen post-MI. Methods: We determined the leukocyte kinetics by flow cytometry and quantitated resolution metabolome using mass spectrometry in C57BL/6 mice after permanent coronary ligation. Results: Lipid Mediator metabololipidomic analyses revealed that spleen not only serves as a leukocyte reservoir but it also participates actively in SPMs production post-MI. Post-MI leukocyte (CD11b + Ly6G + CD206 + ) turnover at d1 linked to increased SPMs levels in the infarcted LV with marked increase of resolvin (Rv)D1, RvD3-6, maresin (MaR)1, lipoxins (LX) and protectin D1 compared to d0 naïve controls and d5 post-MI. Before MI, SPMs such as RvD5, RvD6, protectin (PD)1, AT-PD1, MaR1, LXA 4 , AT-LXA 4 , AT-LXB 4 , were higher in spleen than LV indicating that splenic leukocytes mobilize SPMs to activate the healing program in LV post-MI. Lipoxygenase (LOX -5, -12 and -15) were preferentially activated in LV, while cyclooxygenase (COX-1 and -2) in the spleen post-MI. MI-induced comprehensive leukocyte analyses provided the self-regulating means of pro-inflammatory and resolving neutrophils (CD11b + Ly6G + CD206 + ) and macrophages (CD11b + Ly6C hi CD206 + ) in a time dependent manner in the infarcted LV but to a lesser extent in the spleen. Thus, the splenic storage of SPMs, generation of increase LOX-mediated SPMs in the infarcted LV and COX-mediated prostanoids in the spleen facilitates the MI-induced murine LV healing post-MI. Conclusions: The abundance of SPMs in the spleen before MI and amplified SPMs generation in the infarcted LV within 24 hours post-MI confirms that splenic leukocytes determine the murine self-healing post-MI. Thus, the acute phase coincides with the resolving response post-MI and demands investigation of the SPMs role in heart failure pathology.