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

ABSTRACT: 12/15 lipoxygenase (LOX) directs inflammation and lipid remodeling. However, the role of 12/15LOX in post-myocardial infarction (MI) left ventricular remodeling is unclear. To determine the role of 12/15LOX, 8-12?week-old C57BL/6?J wild-type (WT; n?=?93) and 12/15LOX-/- (n?=?97) mice were subjected to permanent coronary artery ligation and monitored at day (d)1 and d5 post-operatively. Post-MI d28 survival was measured in male and female mice. No-MI surgery mice were maintained as d0 naïve controls. 12/15LOX-/- mice exhibited higher survival rates with lower cardiac rupture and improved LV function as compared with WT post-MI. Compared to WT, neutrophils and macrophages in 12/15LOX-/- mice were polarized towards N2 and M2 phenotypes, respectively, with increased of expression mrc-1, ym-1, and arg-1 post-MI. 12/15LOX-/- mice exhibited lower levels of pro-inflammatory 12-(S)-hydroperoxyeicosatetraenoic acid (12(S)-HETE) and higher CYP2J-derived epoxyeicosatrienoic acids (EETs) levels. CYP2J-derived 5,6-, 8,9-, 11,12-, and 14,15-EETs activated macrophage-specific hemeoxygenase (HO)-1 marked with increases in F4/80+/Ly6Clow and F4/80+/CD206high cells at d5 post-MI in 12/15LOX-/- mice. In contrast, inhibition of HO-1 led to total mortality in 12/15LOX-/- mice by post-MI d5. 12/15LOX-/- mice exhibited reduced collagen density and lower ?-smooth muscle actin (SMA) expression at d5 post-MI, indicating delayed or limited fibroblast-to-myofibroblast differentiation. In conclusion, genetic deletion of 12/15LOX reduces 12(S)-HETE and activates CYP2J-derived EETs to promote effective resolution of inflammation post-MI leading to reduced cardiac rupture, improved LV function, and better survival.

SUBMITTER: Kain V

PROVIDER: S-EPMC5940552 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Kain Vasundhara V Ingle Kevin A KA Kabarowski Janusz J Barnes Stephen S Limdi Nita A NA Prabhu Sumanth D SD Halade Ganesh V GV

Journal of molecular and cellular cardiology 20180308

12/15 lipoxygenase (LOX) directs inflammation and lipid remodeling. However, the role of 12/15LOX in post-myocardial infarction (MI) left ventricular remodeling is unclear. To determine the role of 12/15LOX, 8-12 week-old C57BL/6 J wild-type (WT; n = 93) and 12/15LOX<sup>-/-</sup> (n = 97) mice were subjected to permanent coronary artery ligation and monitored at day (d)1 and d5 post-operatively. Post-MI d28 survival was measured in male and female mice. No-MI surgery mice were maintained as d0 ...[more]

PMID: 29526491

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

Project description:Lipoxygenases (LOX) form a heterogeneous family of lipid peroxidizing enzymes capable of converting polyunsaturated fatty acids to their hydroperoxy derivatives. They have been implicated in basic cellular processes such as proliferation and differentiation but are also involved in the pathogenesis of various diseases such as inflammatory disorders and atherosclerosis. The catalytic activity of LOXs increases the intracellular peroxide tone, which is an important parameter for expression regulation of redox-sensitive genes. Previously, we showed that induction of 12/15-expression by interleukin-4 profoundly alters the gene expression pattern of human peripheral monocytes, which led to a profound switch of the cellular phenotype. To explore, which of these changes might be a direct consequence of 12/15-LOX expression we stably transfected a permanent human monocytic cell line (U937) with a 12/15-LOX containing eukaryotic expression plasmid and an empty control vector (mock-control). After a multi-step selection procedure a viable clones (12/15-LOX transfectants and mock-transfectants) were isolated and further cultured. We found that 12/15-LOX expression did not significantly alter basic cellular functions and that the cells, which express the 12/15-LOX at similar levels as IL4-treated human monocytes, did not show major functional deficits when compared with the mock-transfectants. However, more detailed comparison of the gene expression profiles of 12/15-LOX transfected cells and that of corresponding mock-transfectants revealed subtle differences. Among the 22,300 genes present on the chip about one half was not expressed regardless whether 12/15-LOX was present in the cells or not. In 12/15-LOX expressing cells 11,000 genes (50 % of the genes present on the chip) and in the corresponding mock-transfectants 10,600 genes (47 % of the genes present on the chip) were expressed. Among the expressed genes only 900 (7 %) were upregulated more than 2-fold and 1,400 (12 %) were down regulated to a similar extent. Among the regulated gene products we detected several connective tissue matrix proteins (collagen isoforms, lamins, fibulins, fibronectins, aggrecans, claudins), extracellular proteinases (serpins, matrix metalloproteinases), tissue inhibitors of metalloproteinases, growth factors and their receptors, and adhesion molecules. In most cases, we did not see simultaneous up- or down-regulation of all family members but rather selective regulatory response of individual proteins (for instance 5-fold upregulation of collagen XV, alpha â??1, but 20-fold downregulation of collagen VII, alpha-1 after 12/15-LOX transfection). These data suggest that induction of 12/15-LOX specifically modifies the gene expression pattern of U937 cells but did not lead to comprehensive alterations. Experiment Overall Design: Cell transfection Experiment Overall Design: The eukaryotic expression vector pcDNA 3 (Invitrogen Life Technologies, Experiment Overall Design: Leek, The Netherlands) bearing the complete coding region of the rabbit Experiment Overall Design: reticulocyte type 15-LOX1 and a corresponding empty vector (mock) were Experiment Overall Design: transfected into U937 cells using FuGENE 6, according to the manufacturerâ??s instructions. Experiment Overall Design: Briefly, 2.5 x 10E5 cells/ml were plated on 35-mm plates and transfected with 2 Âµg of plasmid using 6 Âµl of FuGENE 6 reagent. After 72h exposure, the precipitate was removed and the cells were cultured for 4 weeks in selection medium supplemented with 0.5 mg/ml geneticin. Experiment Overall Design: Incubation: at 37 Â°C with 5% CO2

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

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

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