NYMC Faculty Publications

Macrophage-Specific Lipoxygenase Deletion Amplify Cardiac Repair Activating Tregcells in Chronic Heart Failure

Author Type(s)

Faculty

DOI

10.1093/jleuko/qiae113

Journal Title

Journal of Leukocyte Biology

First Page

864

Last Page

875

Document Type

Article

Publication Date

10-1-2024

Department

Medicine

Keywords

bioactive lipids, cardiac fibrosis, heart failure, inflammation-resolution signaling, leukocytes, lipid mediators

Disciplines

Medicine and Health Sciences

Abstract

Splenic leukocytes, particularly macrophage-expressed lipoxygenases, facilitate the biosynthesis of resolution mediators essential for cardiac repair. Next, we asked whether deletion of 12/15 lipoxygenase (12/15LOX) in macrophages impedes the resolution of inflammation following myocardial infarction (MI). Using 12/15flox/flox and LysMcre scheme, we generated macrophage-specific 12/15LOX (MΦ-12/15LOX-/-) mice. Young C57BL/6J wild-type and MΦ-12/15LOX-/- male mice were subjected to permanent coronary ligation microsurgery. Mice were monitored at day 1 (d1) to d5 (as acute heart failure [AHF]) and to d56 (chronic HF) post-MI, maintaining no MI as d0 naïve control animals. Post ligation, MΦ-12/15LOX-/- mice showed increased survival (88% vs 56%) and limited heart dysfunction compared with wild-type. In AHF, MΦ-12/15LOX-/- mice have increased biosynthesis of epoxyeicosatrienoic acid by 30%, with the decrease in D-series resolvins, protectin, and maresin by 70% in the infarcted heart. Overall, myeloid cell profiling from the heart and spleen indicated that MΦ-12/15LOX-/- mice showed higher immune cells with reparative Ly6Clow macrophages during AHF. In addition, the detailed immune profiling revealed reparative macrophage phenotype (Ly6Clow) in MΦ-12/15LOX-/- mice in a splenocardiac manner post-MI. MΦ-12/15LOX-/- mice showed an increase in myeloid population that coordinated increase of T regulatory cells (CD4+/Foxp3+) in the spleen and injured heart at chronic HF compared with wild-type. Thus, macrophage-specific deletion of 12/15LOX directs reparative macrophage phenotype to facilitate cardiac repair. The presented study outlines the complex role of 12/15LOX in macrophage plasticity and T regulatory cell signaling that indicates that resolution mediators are viable targets to facilitate cardiac repair in HF post-MI.

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