Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-κB in THP-1 macrophages

Wang, Guoping; Siow, Yaw L.; Karmin, O

doi:10.1152/ajpheart.2001.280.6.h2840

Cited by 89 publications

(58 citation statements)

References 44 publications

(69 reference statements)

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“…36 Oxidative stress is often cited as the mechanism responsible for the injurious effects of HHcy on cultured cells and intact tissues. HHcy activates NF-B in cultured endothelial cells, smooth muscle cells, and macrophages through oxidative stress, [37][38][39] and induction of HHcy in apoE Ϫ/Ϫ mice leads to vascular inflammation and NF-B activation. 5 Thus, our observations of increased HSP70 and phospho-IB-␣ immunostaining in the advanced atherosclerotic lesions as well as increased dihydroethidium staining in the carotid arteries of hyperhomocysteinemic apoE Ϫ/Ϫ mice are consistent with these findings.…”

Section: Discussionmentioning

confidence: 99%

Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

et al. 2004

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Background-A causal relation between hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Although several cellular stress mechanisms have been proposed to explain the atherogenic effects of HHcy, including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, their association with atherogenesis has not been completely elucidated. Methods and Results-ApoEϪ/Ϫ mice were fed a control or a high-methionine (HM) diet for 4 (early lesion group) or 18 (advanced lesion group) weeks to induce HHcy. Total plasma homocysteine levels and atherosclerotic lesion size were significantly increased in early and advanced lesion groups fed the HM diet compared with control groups. Markers of ER stress (GRP78/94, phospho-PERK), oxidative stress (HSP70), and inflammation (phospho-IB-␣) were assessed by immunohistochemical staining of these atherosclerotic lesions. GRP78/94, HSP70, and phospho-IB-␣ immunostaining were significantly increased in the advanced lesion group fed the HM diet compared with the control group. HSP47, an ER-resident molecular chaperone involved in collagen folding and secretion, was also increased in advanced lesions of mice fed the HM diet. GRP78/94 and HSP47 were predominantly localized to the smooth muscle cell-rich fibrous cap, whereas HSP70 and phospho-IB-␣ were observed in the lipid-rich necrotic core. Increased HSP70 and phospho-IB-␣ immunostaining in advanced lesions of mice fed the HM diet are consistent with enhanced carotid artery dihydroethidium staining. Interestingly, GRP78/94 and phospho-PERK were markedly increased in macrophage foam cells from early lesions of mice fed the control or the HM diet.

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Section: Discussionmentioning

confidence: 99%

Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

et al. 2004

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“…The mechanism for the association between MMP and Hcy is not fully understood. Studies suggest that Hcy might stimulate MMP9 expression via an NF-κB-activating mechanism, resulting in enhanced cytokine production [32] (NF-κB plays an essential role in the transcriptional activation of IL6 induced by various stimuli). Our finding that three different inhibitors of NF-κB activation reversed the Hcy-induced IL6 release in cells grown in low as well as high glucose is in keeping with this view, and the observation of a parallel inhibitory effect of both NAC and calphostin C on MMP release confirms a link between MMP and cytokine production [33].…”

Section: Discussionmentioning

confidence: 99%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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Aims/hypothesis Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. Materials and methods In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Results Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Conclusions/interpretation Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

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“…Treatment of cultured human vascular endothelial cells, smooth muscle cells, and monocytes with homocysteine induces the expression of monocyte chemoattractant protein 1 (MCP-1). [59][60][61] MCP-1 enhances the binding of monocytes to the endothelium and their recruitment to the subendothelial cell space, a critical step in atherosclerotic lesion development. Homocysteine has also been shown to increase expression of IL-8, 59 a T lymphocyte and neutrophil chemoattractant, in cultured endothelial cells.…”

Section: Hhcy and Atherothrombosis: Potential Cellular Mechanisms Infmentioning

confidence: 99%

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

2004

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Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

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Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-κB in THP-1 macrophages

Cited by 89 publications

References 44 publications

Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

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