Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system

Journal of Translational Medicine

Malcolm L Watson¹  Hany M El-Bassossy² 

[1] Department of Pharmacy and Pharmacology, University of Bath, Bath, UK;Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

关键词: Allopurinol;    Xanthine oxidase;    Hypertension;    Heart;    Metabolic syndrome;   

Others  :  1137513
DOI  :  10.1186/s12967-015-0445-9

 received in 2014-10-02, accepted in 2015-02-23,  发布年份 2015

【 摘 要 】

Background

We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.

Methods

IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT₁) were assessed by immunofluorescence.

Results

IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT₁ receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.

Conclusions

XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

【 授权许可】

   
2015 El-Bassossy and Watson; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Kolovou GD, Anagnostopoulou KK, Cokkinos DV: Pathophysiology of dyslipidaemia in the metabolic syndrome. Postgrad Med J 2005, 81:358-66.
• [2]Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. JAMA 2002, 287:356-9.
• [3]Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al.: Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013, 62:3307-15.
• [4]Filiopoulos V, Hadjiyannakos D, Vlassopoulos D: New insights into uric acid effects on the progression and prognosis of chronic kidney disease. Renal Fail 2012, 34:510-20.
• [5]El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML: Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol 2013, 169:693-703.
• [6]Pacher P, Nivorozhkin A, Szabo C: Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006, 58:87-114.
• [7]Struthers A, Shearer F: Allopurinol: novel indications in cardiovascular disease. Heart 2012, 98:1543-5.
• [8]Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG: Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 2010, 160:1577-9.
• [9]Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al.: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006, 290:F625-31.
• [10]El-Bassossy H, Dsokey N, Fahmy A: Characterization of vascular complications in experimental model of fructose induced metabolic syndrome. Toxicol Mech Meth 2014, 29:1-8.
• [11]Field KJ, White WJ, Lang CM: Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats. Lab Anim 1993, 27:258-69.
• [12]Yamamoto S, Matsui K, Sasabe M, Kitano M, Ohashi N: Effect of SMP-300, a new Na+/H+ exchange inhibitor, on myocardial ischemia and experimental angina models in rats. Jpn J Pharmacol 2000, 84:196-205.
• [13]Azhar A, El-Bassossy HM: Pentoxifylline alleviates cardiac ischemia and dysfunction following experimental angina in insulin resistance. PLoS ONE 2014, 9:e98281.
• [14]Mori T, Ishigai Y, Fukuzawa A, Chiba K, Shibano T: Pharmacological profile of semotiadil fumarate, a novel calcium antagonist, in rat experimental angina model. Br J Pharmacol 1995, 116:1668-72.
• [15]Hassan N, El-Bassossy HM, Zakaria MNM: Heme oxygenase-1 induction protects against hypertension associated with diabetes: Effect on exaggerated vascular contractility. Naunyn Schmiedebergs Arch Pharmacol 2013, 386:217-26.
• [16]Hassan NA, El-Bassossy HM, Mahmoud MF, Fahmy A: Caffeic acid phenethyl ester, a 5-lipoxygenase enzyme inhibitor, alleviates diabetic atherosclerotic manifestations: Effect on vascular reactivity and stiffness. Chem Biol Interact 2014, 213:28-36.
• [17]Mahmoud MF, Hassan NA, El Bassossy HM, Fahmy A: Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLoS ONE 2013, 8:e63784.
• [18]Schafer S, Huber J, Wihler C, Rutten H, Busch AE, Linz W: Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of N-(carboxymethyl)lysine. Eur J Heart Fail 2006, 8:2-6.
• [19]Loganathan R, Bilgen M, Al-Hafez B, Alenezy MD, Smirnova IV: Cardiac dysfunction in the diabetic rat: quantitative evaluation using high resolution magnetic resonance imaging. Cardiovas Diabetol 2006, 4:5-7.
• [20]Radovits T, Korkmaz S, Loganathan S, Barnucz E, Bomicke T, Arif R, et al.: Comparative investigation of the left ventricular pressure-volume relationship in rat models of type 1 and type 2 diabetes mellitus. Am J Physiol - Heart Cir Physiol 2009, 297:H125-33.
• [21]Vergeade A, Mulder P, Vendeville C, Ventura-Clapier R, Thuillez C, Monteil C: Xanthine oxidase contributes to mitochondrial ROS generation in an experimental model of cocaine-induced diastolic dysfunction. J Cardiovasc Pharmacol 2012, 60:538-43.
• [22]van Noord C, Eijgelsheim M, Stricker BH: Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010, 70:16-23.
• [23]Miki T, Tobisawa T, Sato T, Tanno M, Yano T, Akasaka H, et al.: Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? Cardiovasc Diabetol 2014, 13:125. BioMed Central Full Text
• [24]Lu Z, Ji A, Taunton J, Lu Y, Shishido T, McClain C, et al.: Reactive oxygen species-induced activation of p90 ribosomal s6 kinase prolongs cardiac repolarization via inhibiting outward K(+) channel activity. Circ Res 2008, 103:269-78.
• [25]Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, et al.: ROS-activated Ca/calmodulin kinase II is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res 2011, 108:555-65.
• [26]Williams IL, Vazir A, Zaman AG: Review: the management of stable angina in diabetes. Br J Diab Vasc Dis 2003, 3:18-25.
• [27]Stone PH: Allopurinol: a new anti-ischemic role for an old drug. J Am Coll Cardiol 2011, 58:829-30.
• [28]Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ: The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013, 99:759-66.
• [29]Heinig M, Johnson RJ: Role of uric acid in hypertension, renal disease, and metabolic syndrome. Cleve Clin J Med 2006, 73:1059-64.
• [30]Pickup JC: Inflammation and Activated Innate Immunity in the Pathogenesis of Type 2 Diabetes. Diabetes Care 2004, 27:813-23.
• [31]Riegersperger M, Covic A, Goldsmith D: Allopurinol, uric acid, and oxidative stress in cardiorenal disease. Inter Urol Nephrol 2011, 43:441-9.
• [32]Gliemann L, Nyberg M, Hellsten Y: Nitric oxide and reactive oxygen species in limb vascular function: What is the effect of physical activity? Free Rad Res 2014, 48:71-83.
• [33]Azhar A, El Bassossy HM. Pentoxifylline alleviates hypertension in metabolic syndrome: effect on low-grade inflammation and angiotensin system. J Endocrinol Invest. 2014. doi:10.1007/s40618-014-0209-z
• [34]El-Bassossy HM, El-Moselhy MA, Mahmoud MF: Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition. Naunyn Schmiedebergs Arch Pharmacol 2011, 384:277-85.
• [35]Demirel U, Yalniz M, Aygün C, Orhan C, Tuzcu M, Sahin K, et al.: Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats. Inflammation 2012, 35:1549-57.
• [36]Frigolet ME, Torres N, Tovar AR: The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 2013, 24:2003-15.
• [37]Jia N, Dong P, Ye Y, Qian C, Dai Q: Allopurinol attenuates oxidative stress and cardiac fibrosis in angiotensin ii-induced cardiac diastolic dysfunction. Cardiovas Ther 2012, 30:117-23.
• [38]Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, et al.: Insulin resistance and cardiovascular events with low HDL cholesterol: the veterans affairs HDL intervention trial (VA-HIT). Diabetes Care 2003, 26:1513-7.
• [39]Wang W, Wang C, Ding XQ, Pan Y, Gu TT, Wang MX, et al.: Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol 2013, 169:1352-71.