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Decreases in 15-lipoxigenase metabolites in Olmsted syndrome model rats

ABSTRACT: Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) is the causative gene of OS and encodes a thermosensitive Ca2+-channel. However, the molecular mechanism causing the pathological development of OS is unclear. We aimed to reveal the molecular mechanism underlying the OS pathology from the perspective of lipid metabolism. Comprehensive lipidomics as well as microarray analyses were conducted on samples from non-lesional skin area of an OS rat model (Ht rats). Infiltration of mast cells, eosinophils, and neutrophils and an increase in fibrotic region were detected in unaffected skin area of Ht rats. Among ~600 lipid species examined, levels of 15-lipoxygenase (LOX) metabolites, the precursors of anti-inflammatory and pro-resolving lipid mediators, and dihydroceramides were decreased by ≥16-fold in Ht rats compared to wild type rats. Consistent with the decreases in the 15-LOX metabolites, expression levels of the 15-LOXs, Alox15 and Alox15b, were largely reduced. On the other hand, expression levels of the cytokines/chemokines Il36b, Ccl20, Cxcl1, and Cxcl2 and those of the Ca2+-binding proteins S100a8 and S100a9, which are implicated in epidermal proliferation, were increased. The pro-inflammatory state of Ht rats caused by decreases in 15-LOX metabolites and increases in cytokines/chemokines may contribute to the pathogenesis of OS.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE84294 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA328604

REPOSITORIES: GEO

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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 –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. Keywords: other

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Decreases in 15-lipoxigenase metabolites in Olmsted syndrome model rats

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