Dataset Information

Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein.

ABSTRACT: Engagement of the receptor for advanced glycation end products (RAGE) by its signal transduction ligands evokes inflammatory cell infiltration and activation of the vessel wall. However, soluble RAGE (sRAGE), the truncated form spanning the extracellular binding domain of RAGE, has potent anti-inflammatory properties by acting as a decoy for RAGE ligands. We now show that sRAGE binds with high affinity to atherogenic low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl), the major oxidant generated by the myeloperoxidase-H2O2-chloride system of phagocytes activated during inflammation. We further demonstrate that sRAGE can be coprecipitated with HOCl-LDL from spiked serum. To determine the functional significance of sRAGE binding to HOCl-LDL, cell association studies with macrophages were performed. sRAGE effectively inhibited cellular uptake of HOCl-LDL and subsequent lipid accumulation. Using Chinese hamster ovary cells overexpressing class B scavenger receptor CD36 or SR-BI, two preferential scavenger receptors for HOCl-LDL, we demonstrate that sRAGE only interferes with CD36-mediated uptake of HOCl-LDL. The present findings indicate that sRAGE acts as a sink for HOCl-LDL, which is abundantly present in human atherosclerotic lesions. We propose that sRAGE represents a physiological antagonist that interferes with scavenger receptor-mediated cholesterol accumulation and foam cell formation of macrophages.

SUBMITTER: Marsche G

PROVIDER: S-EPMC4861206 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein.

Marsche Gunther G Weigle Bernd B Sattler Wolfgang W Malle Ernst E

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20070529 12

Engagement of the receptor for advanced glycation end products (RAGE) by its signal transduction ligands evokes inflammatory cell infiltration and activation of the vessel wall. However, soluble RAGE (sRAGE), the truncated form spanning the extracellular binding domain of RAGE, has potent anti-inflammatory properties by acting as a decoy for RAGE ligands. We now show that sRAGE binds with high affinity to atherogenic low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl), the major o ...[more]

PMID: 17536039

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Project description:Oxidation of low-density lipoprotein (LDL) lipid is thought to represent the initial step in a series of oxidative modification reactions that ultimately transform this lipoprotein into an atherogenic high-uptake form that can cause lipid accumulation in cells. We have studied the effects of hypochlorite, a powerful oxidant released by activated monocytes and neutrophils, on isolated LDL. Exposure of LDL to reagent hypochlorite (NaOCl) at 4 degrees C resulted in immediate and preferential oxidation of amino acid residues of apoprotein B-100, the single protein associated with LDL. Neither lipoprotein lipid nor LDL-associated antioxidants, except ubiquinol-10, represented major targets for this oxidant. Even when high concentrations of NaOCl were used, only low levels of lipid hydroperoxides could be detected with the highly sensitive h.p.l.c. post-column chemiluminescence detection method. Lysine residues of apoprotein B-100 quantitatively represented the major target, scavenging some 68% of the NaOCl added, with tryptophan and cysteine together accounting for an additional 10% of the oxidant. Concomitant with the loss of LDL's amino groups, chloramines were formed and the anionic surface charge of the lipoprotein particle increased, indicated by a 3-4-fold increase in electrophoretic mobility above that of native LDL on agarose gels. While both these changes could be initially reversed by physiological reductants such as ascorbic acid and methionine, incubation of the NaOCl-modified LDL at 37 degrees C resulted in increasing resistance of the modified lysine residues against reductive reversal. Exposure of mouse peritoneal macrophages to NaOCl-oxidized LDL resulted in increased intracellular concentrations of cholesterol and cholesteryl esters. These findings suggest that lipid-soluble antioxidants associated with LDL do not efficiently protect the lipoprotein against oxidative damage mediated by hypochlorite, and that extensive lipid oxidation is not a necessary requirement for oxidative LDL modification that leads to a high-uptake form of the lipoprotein.

Project description:Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood.Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)-null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI(+/+) mice, but no thymocyte apoptosis in SR-BI(-/-) mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI(-/-) mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI(+/+) HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI(-/-) HDL had no such activity. Further study revealed that SR-BI(+/+) HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI(-/-) HDL loses such regulatory activity. To understand why SR-BI(-/-) HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI(-/-) HDL compared with SR-BI(+/+) HDL. Normalization of unesterified cholesterol in SR-BI(-/-) HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI(+/+) HDL rendered SR-BI(+/+) HDL dysfunctional. Using lckCre-GR(fl/fl) mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GR(fl/fl) mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GR(fl/fl) control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis.The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI and HDL.

Dataset Information

Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein.

Publications

Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein.

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