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      Role of TNF-α in vascular dysfunction

      * , , , § , * , , , § , * , , , § , * , , , § , * , , , § , * , , , § , * , , * , , , §
      Clinical Science (London, England : 1979)
      Portland Press Ltd.
      inflammation, macrovascular circulation, microvascular circulation, nitric oxide, reactive oxygen species (ROS), tumour necrosis factor-α (TNF-α), ACEI, angiotensin-converting enzyme inhibitor, AGE, advanced glycation end-product, AMI, acute myocardial infarction, ASS, argininosuccinate synthase, CRP, C-reactive protein, DC, dendritic cell, EC, endothelial cell, EDHF, endothelium-dependent hyperpolarizing factor, EET, epoxyeicosatrienoic acid, EPC, endothelial progenitor cell, HDL, high-density lipoprotein, HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA, HUVEC, human umbilical vein EC, ICAM-1, intercellular adhesion molecule-1, IHD, ischaemic heart disease, IL, interleukin, I/R, ischaemia/reperfusion, NF-κB, nuclear factor κB, IκB, inhibitor of NF-κB, IKK, IκB kinase, NOS, NO synthase, cNOS, constitutive NOS, eNOS, endothelial NOS, iNOS, inducible NOS, nNOS, neuronal NOS, O2•−, superoxide radical, ONOO−, peroxynitrite, PGI2, prostacyclin, RA, rheumatoid arthritis, RAGE, receptor for AGEs, ROS, reactive oxygen species, SCF, stem cell factor, SK1, sphingosine kinase 1, Sph1P, sphingosine-1-phosphate, TNF, tumour necrosis factor, TNFR, TNF receptor, t-PA, tissue plasminogen activator, VCAM-1, vascular cell adhesion molecule-1, XO, xanthine oxidase, ZOF rat, Zucker Obese Fatty rat

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          Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.

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          Most cited references112

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          Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

          To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.
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            Endothelial dysfunction in diabetes.

            Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.
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              Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture).

              Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A2, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

                Author and article information

                Clin Sci (Lond)
                Clinical Science (London, England : 1979)
                Portland Press Ltd.
                8 January 2009
                1 February 2009
                : 116
                : Pt 3
                : 219-230
                *Department of Internal Medicine, University of Missouri, Columbia, MO 65211, U.S.A.
                †Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, U.S.A.
                ‡Department of Nutritional Sciences, University of Missouri, Columbia, MO 65211, U.S.A.
                §Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, U.S.A.
                Author notes
                Correspondence: Professor Cuihua Zhang (email zhangcu@ 123456missouri.edu ).
                © 2009 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, References: 122, Pages: 12
                Review Article

                icam-1, intercellular adhesion molecule-1,o2•−, superoxide radical,acei, angiotensin-converting enzyme inhibitor,il, interleukin,iκb, inhibitor of nf-κb,zof rat, zucker obese fatty rat,scf, stem cell factor,nf-κb, nuclear factor κb,ec, endothelial cell,eet, epoxyeicosatrienoic acid,onoo−, peroxynitrite,inos, inducible nos,microvascular circulation,huvec, human umbilical vein ec,inflammation,sph1p, sphingosine-1-phosphate,reactive oxygen species (ros),cnos, constitutive nos,ra, rheumatoid arthritis,tnf, tumour necrosis factor,hmg-coa, 3-hydroxy-3-methylglutaryl-coa,t-pa, tissue plasminogen activator,pgi2, prostacyclin,crp, c-reactive protein,vcam-1, vascular cell adhesion molecule-1,ass, argininosuccinate synthase,nos, no synthase,ros, reactive oxygen species,rage, receptor for ages,epc, endothelial progenitor cell,xo, xanthine oxidase,hdl, high-density lipoprotein,tumour necrosis factor-α (tnf-α),age, advanced glycation end-product,ami, acute myocardial infarction,nitric oxide,ihd, ischaemic heart disease,i/r, ischaemia/reperfusion,enos, endothelial nos,sk1, sphingosine kinase 1,ikk, iκb kinase,edhf, endothelium-dependent hyperpolarizing factor,tnfr, tnf receptor,nnos, neuronal nos,macrovascular circulation,dc, dendritic cell


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