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A solute carrier family 22 member 3 variant rs3088442 G?A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.

ABSTRACT: Recent genome-wide association studies have identified single-nucleotide polymorphism (SNPs) within the SLC22A3 (solute carrier family 22 member 3) gene associated with coronary heart disease (CHD) in the Caucasian population. We performed molecular analysis to investigate the potential role of SLC22A3 variants in CHD. Our study showed that the common polymorphism rs3088442 G?A, which is localized in the 3' UTR of the SLC22A3 gene, was associated with a decreased risk of CHD in the Chinese population by a case control study. In silico analysis indicated that G?A substitution of SNP rs3088442 created a putative binding site for miR-147 in the SLC22A3 mRNA. By overexpressing miR-147 or inhibiting endogenous miR-147, we demonstrated that SNP rs3088442 G?A recruited miR-147 to inhibit SLC22A3 expression. Moreover, SLC22A3 deficiency significantly decreased LPS-induced monocytic inflammatory response by interrupting NF-?B and MAPK signaling cascades in a histamine-dependent manner. Notably, the expression of SLC22A3(A) was also suppressed by LPS stimulus. Our findings might indicate a negative feedback mechanism against inflammatory response by which SLC22A3 polymorphisms decreased the risk of CHD.

SUBMITTER: Li L

PROVIDER: S-EPMC4342451 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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A solute carrier family 22 member 3 variant rs3088442 G→A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.

Li Lu L He Meian M Zhou Li L Miao Xiaoping X Wu Fangqing F Huang Suli S Dai Xiayun X Wang Tian T Wu Tangchun T

The Journal of biological chemistry 20150105 9

Recent genome-wide association studies have identified single-nucleotide polymorphism (SNPs) within the SLC22A3 (solute carrier family 22 member 3) gene associated with coronary heart disease (CHD) in the Caucasian population. We performed molecular analysis to investigate the potential role of SLC22A3 variants in CHD. Our study showed that the common polymorphism rs3088442 G→A, which is localized in the 3' UTR of the SLC22A3 gene, was associated with a decreased risk of CHD in the Chinese popul ...[more]

PMID: 25561729

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Project description:Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2-/- mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2-/- mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1?, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2-/- mice. In bone marrow chimeras between Slc7a2-/- and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.

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Dataset Information

A solute carrier family 22 member 3 variant rs3088442 G?A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.

Publications

A solute carrier family 22 member 3 variant rs3088442 G→A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.

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