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Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure.

ABSTRACT: Resolvins are innate, immune responsive, bioactive mediators generated after myocardial infarction (MI) to resolve inflammation. The MI-induced bidirectional interaction between progressive left ventricle (LV) remodeling and kidney dysfunction is known to advance cardiorenal syndrome (CRS). Whether resolvins limit MI-induced cardiorenal inflammation is unclear. Thus, to define the role of exogenous resolvin D (RvD)-1 in post-MI CRS, we subjected 8- to 12-wk-old male C57BL/6 mice to coronary artery ligation. RvD1 was injected 3 h after MI. MI mice with no treatment served as MI controls (d 1 and 5). Mice with no surgery served as naive controls. In the injected mice, RvD1 promoted neutrophil (CD11b+/Ly6G+) egress from the infarcted LV, compared with the MI control group at d 5, indicative of neutrophil clearance and thereby resolved inflammation. Further, RvD1-injected mice showed higher reparative macrophages (F4/80+/Ly6Clow/CD206+) in the infarcted LV than did MI control mice at d 5 after MI. RvD1 suppressed the miRNA storm at d 1 and limited the MI-induced edematous milieu in a remote area of the LV compared with the MI control at d 5 after MI. Also, RvD1 preserved the nephrin expression that was diffuse in the glomerular membrane at d 5 and 28 in MI controls, indicating renal injury. RvD1 attenuated MI-induced renal inflammation, decreasing neutrophil gelatinase-associated lipocalin and proinflammatory cytokines and chemokines in the kidney compared with the MI control. In summary, RvD1 clears MI-induced inflammation by increasing resolving leukocytes and facilitates renoprotective mechanisms to limit CRS in acute and chronic heart failure.-Halade, G. V., Kain, V., Serhan, C. N. Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure.

SUBMITTER: Halade GV

PROVIDER: S-EPMC5998972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bioactive lipid mediators derived from n-3 and n-6 fatty acids are known to modulate leukocytes. Metabolic transformation of essential fatty acids to endogenous bioactive molecules plays a major role in human health. Here we tested the potential of substrates; linoleic acid (LA) and docosahexaenoic acid (DHA) and their bioactive products; resolvin D1 (RvD1) and 12- S-hydroxyeicosatetraenoic acids (HETE) to modulate macrophage plasticity and cardiac fibroblast phenotype in presence or absence of lipid metabolizing enzyme 12/15-lipoxygenase (LOX). Peritoneal macrophages and cardiac fibroblasts were isolated from wild-type (C57BL/6J) and 12/15LOX -/- mice and treated with DHA, LA, 12(S)-HETE, and RvD1 for 4, 8, 12, and 24?hr. LA, DHA, 12(S)-HETE, and RvD1 elicited mRNA expression of proinflammatory markers; tumor necrosis factor-? ( Tnf-?), interleukin 6 ( IL-6), chemokine (C-C motif) ligand 2 (Ccl2), and IL-1? in wild type (WT) and in 12/15LOX -/- macrophages at early time point (4?hr). Bioactive immunoresolvent RvD1 lowered the levels of Tnf-?, IL-6, and IL-1? at 24?hr time point. Both DHA and RvD1 stimulated the proresolving markers such as arginase 1 ( Arg-1), chitinase-like protein 3 ( Ym-1), and mannose receptor C-type 1 in WT macrophage. RvD1 induced proresolving phenotype Arg-1 expression in both WT 12/15LOX -/- macrophages even in presence of 12(S)-HETE. RvD1 peaked 5LOX expression in both WT and 12/15LOX -/- at 24?hr time point compared with DHA. RvD1 diminished cyclooxygenase-2 but upregulated 5LOX expression in fibroblast compared with DHA. In summary, the feed-forward enzymatic interaction with fatty acids substrates and direct mediators (RvD1 and 12(S)-HETE) are responsive in determining macrophages phenotype and cardiac fibroblast plasticity. Particularly, macrophages and fibroblast phenotypes are responsive to milieu and RvD1 governs the milieu-dependent chemokine signaling in presence or absence of 12/15LOX enzyme to resolve inflammation.

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Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure.

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