Abstract 12625: Splenic Leukocytes Defines the Resolution of Inflammation and Left Ventricle Healing in Heart Failure Pathology
DOI:
10.1161/circ.134.suppl_1.12625
Publication Date:
2024-04-23T10:55:56Z
AUTHORS (6)
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.
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