High Fat Feeding Impairs Endothelin-1 Mediated Vasoconstriction Through Increased iNOS-derived Nitric Oxide

Abstract

Rats fed a high fat diet develop increased adiposity and oxidative stress leading to impaired vasodilation. The purpose of the present study was to examine the effects of high fat-induced increases in adiposity and oxidative stress on vasoconstrictor reactivity of isolated mesenteric arteries. We hypothesized that rats with more adiposity would develop oxidative stress-potentiated increases in iNOS-derived nitric oxide leading to diminished vasoconstriction. Male Sprague-Dawley rats were fed either a control (Chow) or high fat diet for 6 weeks. The roles of oxidative stress and iNOS in the impaired vasoconstrictor responses to endothelin-1 were characterized in small mesenteric arteries. Rats fed the HFD developed significantly more adiposity compared to Chow rats. Plasma levels of nitric oxide and the inflammatory factor tumor necrosis factor α were significantly higher in high fat fed rats compared to Chow rats (nitric oxide: 95.36±19.3 vs. 38.96±6.7 μM; tumor necrosis factor α: 598±111.4 vs. 292±71.8 pg/ml, respectively). Despite exhibiting elevated systolic blood pressure compared to Chow rats (153.5±2.4 vs. 137.5±2.7 mm Hg), endothelin-1 mediated vasoconstriction was impaired in isolated mesenteric arteries from high fat fed rats but was normalized by individual or combined inhibition of nitric oxide synthase, iNOS, or oxidative stress. Therefore, oxidative stress and iNOS are involved in the attenuation of endothelin-1 mediated vasoconstriction observed in isolated mesenteric arteries from high fat fed rats.

Key words

oxidative stress - overweight - antioxidant - inflammation - mesenteric artery

References

• 1 Montani JP, Antic V, Yang Z, Dulloo A. Pathways from obesity to hypertension: from the perspective of a vicious triangle.  Int J Obes Relat Metab Disord. 2002;  26 (S 02) S28-S38
• 2 Kim JK, Wi JK, Youn JH. Metabolic impairment precedes insulin resistance in skeletal muscle during high-fat feeding in rats.  Diabetes. 1996;  45 651-658
• 3 Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats.  Am J Physiol. 1986;  251 E576-E583
• 4 Viswanad B, Srinivasan K, Kaul CL, Ramarao P. Effect of tempol on altered angiotensin II and acetylcholine-mediated vascular responses in thoracic aorta isolated from rats with insulin resistance.  Pharmacol Res. 2006;  53 209-215
• 5 Sweazea KL, Lekic M, Walker BR. Comparison of mechanisms involved in impaired vascular reactivity between high sucrose and high fat diets in rats.  Nutr Metab (Lond). 2010;  7 48
• 6 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.  J Clin Invest. 2004;  114 1752-1761
• 7 Mason C, Craig CL, Katzmarzyk PT. Influence of central and extremity circumferences on all-cause mortality in men and women.  Obesity (Silver Spring). 2008;  16 2690-2695
• 8 Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms.  Hypertension. 2003;  42 1075-1081
• 9 Mungrue IN, Bredt DS, Stewart DJ, Husain M. From molecules to mammals: what's NOS got to do with it?.  Acta Physiol Scand. 2003;  179 123-135
• 10 Haque MM, Panda K, Tejero J, Aulak KS, Fadlalla MA, Mustovich AT, Stuehr DJ. A connecting hinge represses the activity of endothelial nitric oxide synthase.  Proc Natl Acad Sci USA. 2007;  104 9254-9259
• 11 Mastronardi CA, Yu WH, McCann SM. Resting and circadian release of nitric oxide is controlled by leptin in male rats.  Proc Natl Acad Sci USA. 2002;  99 5721-5726
• 12 Noronha BT, Li JM, Wheatcroft SB, Shah AM, Kearney MT. Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity.  Diabetes. 2005;  54 1082-1089
• 13 Beck KF, Eberhardt W, Walpen S, Apel M, Pfeilschifter J. Potentiation of nitric oxide synthase expression by superoxide in interleukin 1 beta-stimulated rat mesangial cells.  FEBS Lett. 1998;  435 35-38
• 14 Wu F, Cepinskas G, Wilson JX, Tyml K. Nitric oxide attenuates but superoxide enhances iNOS expression in endotoxin- and IFNgamma-stimulated skeletal muscle endothelial cells.  Microcirculation. 2001;  8 415-425
• 15 Heusch P, Aker S, Boengler K, Deindl E, van de Sand A, Klein K, Rassaf T, Konietzka I, Sewell A, Menazza S, Canton M, Heusch G, Di Lisa F, Schulz R. Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S-nitrosylation.  Am J Physiol Heart Circ Physiol. 2010;  299 H446-H453
• 16 Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms of obesity-induced hypertension.  Hypertens Res. 2010;  33 386-393
• 17 Despres JP. Cardiovascular disease under the influence of excess visceral fat.  Crit Pathw Cardiol. 2007;  6 51-59
• 18 Feldstein C, Julius S. The complex interaction between overweight, hypertension, and sympathetic overactivity.  J Am Soc Hypertens. 2009;  3 353-365
• 19 Baker K, Marcus CB, Huffman K, Kruk H, Malfroy B, Doctrow SR. Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury.  J Pharmacol Exp Ther. 1998;  284 215-221
• 20 Korner J, Woods SC, Woodworth KA. Regulation of energy homeostasis and health consequences in obesity.  Am J Med. 2009;  122 S12-S18
• 21 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue – an update.  Horm Metab Res. 2007;  39 314-321
• 22 Ketonen J, Shi J, Martonen E, Mervaala E. Periadventitial Adipose Tissue Promotes Endothelial Dysfunction via Oxidative Stress in Diet-Induced Obese C57Bl/6 Mice.  Circ J. 2010;  74 1479-1487
• 23 Lee CH, Poburko D, Sahota P, Sandhu J, Ruehlmann DO, van Breemen C. The mechanism of phenylephrine-mediated [Ca(2+)](i) oscillations underlying tonic contraction in the rabbit inferior vena cava.  J Physiol. 2001;  534 641-650
• 24 Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels.  Circulation. 1994;  89 1203-1208
• 25 Simonson MS, Wann S, Mene P, Dubyak GR, Kester M, Dunn MJ. Endothelin-1 activates the phosphoinositide cascade in cultured glomerular mesangial cells.  J Cardiovasc Pharmacol. 1989;  13 (S 05) S80-S84
• 26 Tsukahara H, Ende H, Magazine HI, Bahou WF, Goligorsky MS. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase.  J Biol Chem. 1994;  269 21778-21785
• 27 Zhang Y, Brovkovych V, Brovkovych S, Tan F, Lee BS, Sharma T, Skidgel RA. Dynamic receptor-dependent activation of inducible nitric-oxide synthase by ERK-mediated phosphorylation of Ser745.  J Biol Chem. 2007;  282 32453-32461

Correspondence