Preserved endothelial function in human obesity in the absence of insulin resistance

Journal of Translational Medicine

Leocadio Rodríguez-Mañas⁴  Alberto Hernández Matías⁵  María Luz Pindado Martínez¹  Javier Angulo²  Juan Carlos Ruiz de Adana⁵  Mariam El Assar³ 

[1] Servicio de Anestesiología y Reanimación, Hospital Universitario de Getafe, Madrid, Spain;Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain;Fundación para la Investigación Biomédica, Hospital Universitario de Getafe, Madrid, Spain;Servicio de Geriatría, Hospital Universitario de Getafe, Madrid, Spain;Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario de Getafe, Madrid, Spain

关键词: Mitochondria;    Inflammation;    Oxidative stress;    Nitric oxide;    Endothelial dysfunction;    Obesity;    Insulin resistance;   

Others  :  825012
DOI  :  10.1186/1479-5876-11-263

 received in 2013-07-30, accepted in 2013-10-14,  发布年份 2013

【 摘 要 】

Background

Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, obesity has long been related to IR and increased CVD. However it is not known if IR is a necessary condition for endothelial dysfunction in human obesity, allowing for preserved endothelial function in obese people when absent. Therefore, the purpose of the study was to assess the relationship between IR and endothelial dysfunction in human obesity and the mechanisms involved.

Methods

Twenty non-insulin resistant morbid obese (NIR-MO), 32 insulin resistant morbid obese (IR-MO), and 12 healthy subjects were included. Serum concentrations of glucose, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), resistin and adiponectin were determined. IR was evaluated by HOMA-index. Endothelium-dependent relaxation to bradykinin (BK) in mesenteric microvessels was assessed in wire myograph.

Results

Serum IL-6, and TNF-α levels were elevated only in IR-MO patients while resistin was elevated and adiponectin reduced in all MO individuals. Mesenteric arteries from IR-MO, but not from NIR-MO subjects displayed blunted relaxation to BK. Vasodilatation was improved in IR-MO arteries by the superoxide scavenger, superoxide dismutase (SOD) or the mitochondrial-targeted SOD mimetic, mito-TEMPO. NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations. Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO. Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.

Conclusions

Endothelial dysfunction is observed in human morbid obesity only when insulin resistance is present. Mechanisms involved include augmented mitochondrial superoxide generation, and increased systemic inflammation mediated by TNF-α. These findings may explain the different vascular risk of healthy vs unhealthy obesity.

【 授权许可】

   
2013 El Assar et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world–a growing challenge. N Engl J Med 2007, 356:213-215.
• [2]Vanhoutte PM: Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J 2009, 73:595-601.
• [3]Kearney MT, Duncan ER, Kahn M, Wheatcroft SB: Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Exp Physiol 2008, 93:158-163.
• [4]Meyers MR, Gokce N: Endothelial dysfunction in obesity: etiological role in atherosclerosis. Curr Opin Endocrinol Diabetes Obes 2007, 14:365-369.
• [5]Bagi Z, Feher A, Cassuto J: Microvascular responsiveness in obesity: implications for therapeutic intervention. Br J Pharmacol 2012, 165:544-560.
• [6]Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD: Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996, 97:2601-2610.
• [7]Vazzana N, Santilli F, Sestili S, Cuccurullo C, Davi G: Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Curr Med Chem 2011, 18:5267-5280.
• [8]Reaven GM: Insulin resistance: the link between obesity and cardiovascular disease. Med Clin North Am 2011, 95:875-892.
• [9]Singer G, Granger DN: Inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. Microcirculation 2007, 14:375-387.
• [10]Eringa EC, Bakker W, Smulders YM, Serne EH, Yudkin JS, Stehouwer CD: Regulation of vascular function and insulin sensitivity by adipose tissue: focus on perivascular adipose tissue. Microcirculation 2007, 14:389-402.
• [11]Ridker PM, Rifai N, Stampfer MJ, Hennekens CH: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000, 101:1767-1772.
• [12]Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E: Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000, 101:2149-2153.
• [13]Giugliano F, Esposito K, Di Palo C, Ciotola M, Giugliano G, Marfella R, D'Armiento M, Giugliano D: Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. J Endocrinol Invest 2004, 27:665-669.
• [14]Wallace TM, Levy JC, Matthews DR: Use and abuse of HOMA modeling. Diabetes Care 2004, 27:1487-1495.
• [15]Ascaso JF, Romero P, Real JT, Priego A, Valdecabres C, Carmena R: [Insulin resistance quantification by fasting insulin plasma values and HOMA index in a non-diabetic population]. Med Clin (Barc) 2001, 117:530-533.
• [16]Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28:412-419.
• [17]Rodriguez-Mañas L, Angulo J, Vallejo S, Peiro C, Sanchez-Ferrer A, Cercas E, Lopez-Doriga P, Sanchez-Ferrer CF: Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature. Diabetologia 2003, 46:556-566.
• [18]Rodriguez-Mañas L, El-Assar M, Vallejo S, Lopez-Doriga P, Solis J, Petidier R, Montes M, Nevado J, Castro M, Gomez-Guerrero C, et al.: Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell 2009, 8:226-238.
• [19]Ali MI, Ketsawatsomkron P, de Chantemele EJ B, Mintz JD, Muta K, Salet C, Black SM, Tremblay ML, Fulton DJ, Marrero MB, Stepp DW: Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. Circ Res 2009, 105:1013-1022.
• [20]Galvao R, Plavnik FL, Ribeiro FF, Ajzen SA, Christofalo DM, Kohlmann O Jr: Effects of different degrees of insulin sensitivity on endothelial function in obese patients. Arq Bras Cardiol 2012, 98:45-51.
• [21]Lupattelli G, Vuono SD, Boni M, Helou R, Mannarino MR, Roscini AR, Alaeddin A, Pirro M, Vaudo G: Insulin Resistance and not BMI is the Major Determinant of Early Vascular Impairment in Patients with Morbid Obesity. J Atheroscler Thromb 2013. http://dx.doi.org/10.5551/jat.18663 webcite
• [22]Rudofsky G, Roeder E, Merle T, Hildebrand M, Nawroth PP, Wolfrum C: Weight loss improves endothelial function independently of ADMA reduction in severe obesity. Horm Metab Res 2011, 43:343-348.
• [23]Naka KK, Papathanassiou K, Bechlioulis A, Pappas K, Kazakos N, Kanioglou C, Kostoula A, Vezyraki P, Makriyiannis D, Tsatsoulis A, Michalis LK: Effects of pioglitazone and metformin on vascular endothelial function in patients with type 2 diabetes treated with sulfonylureas. Diab Vasc Dis Res 2012, 9:52-58.
• [24]Grassi G, Diez J: Obesity-related cardiac and vascular structural alterations: beyond blood pressure overload. J Hypertens 2009, 27:1750-1752.
• [25]Virdis A, Santini F, Colucci R, Duranti E, Salvetti G, Rugani I, Segnani C, Anselmino M, Bernardini N, Blandizzi C, et al.: Vascular generation of tumor necrosis factor-alpha reduces nitric oxide availability in small arteries from visceral fat of obese patients. J Am Coll Cardiol 2011, 58:238-247.
• [26]Ketonen J, Pilvi T, Mervaala E: Caloric restriction reverses high-fat diet-induced endothelial dysfunction and vascular superoxide production in C57Bl/6 mice. Heart Vessels 2010, 25:254-262.
• [27]Kobayasi R, Akamine EH, Davel AP, Rodrigues MA, Carvalho CR, Rossoni LV: Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice. J Hypertens 2010, 28:2111-2119.
• [28]Lobato NS, Filgueira FP, Akamine EH, Davel AP, Rossoni LV, Tostes RC, Carvalho MH, Fortes ZB: Obesity induced by neonatal treatment with monosodium glutamate impairs microvascular reactivity in adult rats: role of NO and prostanoids. Nutr Metab Cardiovasc Dis 2011, 21:808-816.
• [29]Vasquez-Vivar J, Kalyanaraman B, Martasek P: The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res 2003, 37:121-127.
• [30]Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, Harrison DG, Dikalov SI: Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 2010, 107:106-116.
• [31]Pung YF, Rocic P, Murphy MP, Smith RA, Hafemeister J, Ohanyan V, Guarini G, Yin L, Chilian WM: Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats. Arterioscler Thromb Vasc Biol 2012, 32:325-334.
• [32]Raha S, Robinson BH: Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 2000, 25:502-508.
• [33]Sivitz WI, Yorek MA: Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 2010, 12:537-577.
• [34]Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, et al.: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003, 34:267-273.
• [35]Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, et al.: Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003, 100:8466-8471.
• [36]Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, et al.: Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A 2009, 106:17787-17792.
• [37]Orshal JM, Khalil RA: Reduced endothelial NO-cGMP-mediated vascular relaxation and hypertension in IL-6-infused pregnant rats. Hypertension 2004, 43:434-444.
• [38]Myung SC, Han JH, Song KK, Kang GH, Lee SY, Kim TH, Lee MY, Kim HW, Kim SC: The effects of interleukin-6 on the contraction and relaxation responses of the cavernous smooth muscle from rats. Eur J Pharmacol 2008, 589:228-232.
• [39]Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, Jeziorska M, Laing I, Yates AP, Pemberton PW, Malik RA, Heagerty AM: Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 2009, 119:1661-1670.
• [40]Busik JV, Mohr S, Grant MB: Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes 2008, 57:1952-1965.
• [41]Garcia De La Torre N, Rubio MA, Bordiu E, Cabrerizo L, Aparicio E, Hernandez C, Sanchez-Pernaute A, Diez-Valladares L, Torres AJ, Puente M, Charro AL: Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab 2008, 93:4276-4281.