Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia

Wang, Guoping; Woo, Connie W.; Sung, Fion L.; Siow, Yaw L.; Karmin, O

doi:10.1161/01.atv.0000035404.18281.37

Cited by 132 publications

(92 citation statements)

References 30 publications

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“…Recent studies have reported a significant increase in monocyte binding to the surface of aortic endothelium in rats with diet-induced HHcy. 31 Given that B cell-to-plasma cell differentiation requires XBP-1, 32 a transcriptional activator that amplifies the expression of UPR genes, including GRP78 and GRP94, 33 it is possible that the binding of monocytes to the endothelium and their subsequent differentiation into macrophage foam cells may require XBP-1, thereby accounting for the increased expression of GRP78/94. Because macrophage foam cells readily endocytose both native and oxidized forms of plasma LDL, the accumulation of lipids could potentially elicit an ER stress response.…”

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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“…Recent studies have now demonstrated that the binding of monocytes to the endothelium is significantly elevated in rats with diet-induced HHcy, although typical atherosclerotic lesions were not observed. 115 The increased expression of MCP-1, VCAM-1, and E-selectin in the aortic endothelium of hyperhomocysteinemic rats suggests a potential cellular mechanism responsible for the enhanced monocyte binding and recruitment. The additional observation that supplementation of the diets with folic acid prevented an increase in total plasma homocysteine levels, decreased monocyte binding to the endothelium, and inhibited the expression MCP-1, VCAM-1, and E-selectin further supports an antiatherogenic effect of lowering plasma homocysteine.…”

Section: Animal Models Of Hhcy-induced Atherogenesismentioning

confidence: 98%

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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“…Hyperhomocysteinemia (HHcy) has been implicated as an independent risk factor for coronary heart disease (13). Hcy is a potent proinflammatory factor and promotes inflammation both in vitro and in vivo (14,15). We previously demonstrated that Hcy induces expression and secretion of proinflammatory factors macrophage chemoattractant protein-1 and IL-8 by the mediation of oxidative stress in human monocytes (16,17).…”

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confidence: 99%

Homocysteine Upregulates Resistin Production From Adipocytes In Vivo and In Vitro

Jiang

Gao

et al. 2008

Diabetes

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OBJECTIVE—Homocysteine (Hcy) is epidemiologically related to insulin resistance, which has been speculated to be a low-grade systemic inflammatory condition. Resistin acts as a critical mediator of insulin resistance associated with inflammatory conditions. We aimed to determine whether Hcy can induce insulin resistance by directly regulating the expression and secretion of resistin from adipose tissue. RESEARCH DESIGN AND METHODS—The effect of Hcy on the expression and secretion of resistin and insulin resistance was investigated using primary rat adipocytes and mice with hyperhomocysteinemia (HHcy). RESULTS—Hcy impaired glucose transport and, particularly, the insulin signaling pathway as shown by decreased insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS)-1, increased serine phosphorylation of IRS-1, and inhibited Akt phosphorylation both in vitro and in vivo, and these impairments were accompanied by an increase in resistin expression. Compared with normal mice, HHcy mice with a clinically relevant level of plasma Hcy (19 μmol/l) showed significantly increased resistin production from adipose tissue (33.38 ± 3.08 vs. 19.27 ± 1.71 ng/ml, P < 0.01). Hcy (300–1000 μmol/l) also increased mRNA expression of resistin in primary rat adipocytes in a time- and concentration-dependent manner, with maximal induction at 24 h of approximately fourfold with 1,000 μmol/l. In addition, Hcy-induced resistin expression attenuated by treatment with reactive oxygen species (ROS) scavengers, protein kinase C (PKC), and nuclear factor (NF)-κB inhibitors implies a role in the process for ROS, PKC, and NF-κB. CONCLUSIONS—HHcy may promote insulin resistance through the induction of resistin expression and secretion from adipocytes via the activation of the ROS-PKC–NF-κB pathway.

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Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia

Cited by 132 publications

References 30 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

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Homocysteine Upregulates Resistin Production From Adipocytes In Vivo and In Vitro

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