Abstract
To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-α significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-α, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.
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Nathan DM, Meigs J, Singer DE : The epidemiology of cardiovascular disease in type 2 diabetes mellitus: how sweet it is ... or is it? Lancet 1997; 350: S14–S19.
Wilson PW, D'Agostino RB, Sullivan L, Parise H, Kannel WB : Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 2002; 162: 1867–1872.
Furumoto T, Saito N, Dong J, Mikami T, Fujii S, Kitabatake A : Association of cardiovascular risk factors and endothelial dysfunction in Japanese hypertensive patients: implications for early atherosclerosis. Hypertens Res 2002; 25: 475–480.
Landmesser U, Hornig B, Drexler H : Endothelial function: a critical determinant in atherosclerosis? Circulation 2004; 109: II27–II33.
Brunner H, Cockcroft JR, Deanfield J, et al: Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005; 23: 233–246.
Feletou M, Vanhoutte PM : Endothelial dysfunction: a multifaceted disorder (the Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 2006; 291: H985–H1002.
Cai H, Harrison DG : Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840–844.
Hotamisligil GS, Shargill NS, Spiegelman BM : Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.
Rotter V, Nagaev I, Smith U : Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 2003; 278: 45777–45784.
Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Kober L, Torp-Pedersen C : Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation 2003; 108: 1815–1821.
Wassmann S, Stumpf M, Strehlow K, et al: Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res 2004; 94: 534–541.
Chen XL, Zhang Q, Zhao R, Medford RM : Superoxide, H2O2, and iron are required for TNF-alpha–induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. Am J Physiol Heart Circ Physiol 2004; 286: H1001–H1007.
Bianchi M, Bloom O, Raabe T, et al: Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J Exp Med 1996; 183: 927–936.
Kitamura K, Kangawa K, Kawamoto M, et al: Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993; 192: 553–560.
Shindo T, Kurihara Y, Nishimatsu H, et al: Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation 2001; 104: 1964–1971.
Nishimatsu H, Suzuki E, Nagata D, et al: Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res 2001; 89: 63–70.
Suzuki E, Nagata D, Yoshizumi M, et al: Reentry into the cell cycle of contact-inhibited vascular endothelial cells by a phosphatase inhibitor: possible involvement of extracellular signal–regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 2000; 275: 3637–3644.
Nishimatsu H, Suzuki E, Satonaka H, et al: Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats. Am J Physiol Heart Circ Physiol 2005; 288: H1770–H1776.
Gao X, Belmadani S, Picchi A, et al: Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation 2007; 115: 245–254.
Yang B, Rizzo V : TNF-alpha potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 2007; 292: H954–H962.
Picchi A, Gao X, Belmadani S, et al: Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 2006; 99: 69–77.
Kim F, Gallis B, Corson MA : TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am J Physiol Cell Physiol 2001; 280: C1057–C1065.
Anderson HD, Rahmutula D, Gardner DG : Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells. J Biol Chem 2004; 279: 963–969.
Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I : Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002; 106: 1439–1441.
Calabro P, Willerson JT, Yeh ET : Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 2003; 108: 1930–1932.
Wang CH, Li SH, Weisel RD, et al: C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003; 107: 1783–1790.
Chang JW, Kim CS, Kim SB, Park SK, Park JS, Lee SK : C-reactive protein induces NF-kappaB activation through intracellular calcium and ROS in human mesangial cells. Nephron Exp Nephrol 2005; 101: e165–e172.
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Nishimatsu, H., Suzuki, E., Takeda, R. et al. Blockade of Endogenous Proinflammatory Cytokines Ameliorates Endothelial Dysfunction in Obese Zucker Rats. Hypertens Res 31, 737–743 (2008). https://doi.org/10.1291/hypres.31.737
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DOI: https://doi.org/10.1291/hypres.31.737
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