Superoxide Dismutase Activity in Small Mesenteric Arteries Is Downregulated by Angiotensin II but Not by Hypertension

  • Kang, Kyu-Tae (College of Pharmacy, Duksung Innovative Drug Center, Duksung Women's University) ;
  • Sullivan, Jennifer C. (Department of Physiology, Augusta University) ;
  • Pollock, Jennifer S. (Medical College of Georgia, Augusta University)
  • Received : 2018.08.31
  • Accepted : 2018.09.10
  • Published : 2018.10.15


Many studies reported reduced antioxidant capacity in the vasculature under hypertensive conditions. However, little is known about the effects of antihypertensive treatments on the regulation of vascular antioxidant enzymes. Thus, we hypothesized that antihypertensive treatments prevent the reduction of antioxidant enzyme activity and expression in the small vessels of angiotensin II-induced hypertensive rats (ANG). We observed the small mesenteric arteries and small renal vessels of normotensive rats (NORM), ANG, and ANG treated with a triple antihypertensive therapy of reserpine, hydrochlorothiazide, and hydralazine (ANG + TTx). Systolic blood pressure was increased in ANG, which was attenuated by 2 weeks of triple therapy (127, 191, and 143 mmHg for NORM, ANG, and ANG + TTx, respectively; p < 0.05). Total superoxide dismutase (SOD) activity in the small mesenteric arteries of ANG was lower than that of NORM. The protein expression of SOD1 was lower in ANG than in NORM, whereas SOD2 and SOD3 expression was not different between the groups. Reduced SOD activity and SOD1 expression in ANG was not restored in ANG + TTx. Both SOD activity and SOD isoform expression in the small renal vessels of ANG were not different from those of NORM. Interestingly, SOD activity in the small renal vessels was reduced by TTx. Between groups, there was no difference in catalase activity or expression in both the small mesenteric arteries and small renal vessels. In conclusion, SOD activity in the small mesenteric arteries decreased by angiotensin II administration, but not by hypertension, which is caused by decreased SOD1 expression.


Supported by : National Institutes of Health, National Research Foundation of Korea (NRF)


  1. Lee, M.Y. and Griendling, K.K. (2008) Redox signaling, vascular function, and hypertension. Antioxid. Redox. Signal., 10, 1045-1059.
  2. Cai, H. and Harrison, D.G. (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ. Res., 87, 840-844.
  3. Lip, G.Y., Edmunds, E., Nuttall, S.L., Landray, M.J., Blann, A.D. and Beevers, D.G. (2002) Oxidative stress in malignant and non-malignant phase hypertension. J. Hum. Hypertens., 16, 333-336.
  4. Higashi, Y., Sasaki, S., Nakagawa, K., Matsuura, H., Oshima, T. and Chayama, K. (2002) Endothelial function and oxidative stress in renovascular hypertension. N. Engl. J. Med., 346, 1954-1962.
  5. Wu, R., Millette, E., Wu, L. and de Champlain, J. (2001) Enhanced superoxide anion formation in vascular tissues from spontaneously hypertensive and desoxycorticosterone acetate-salt hypertensive rats. J. Hypertens., 19, 741-748.
  6. Beswick, R.A., Zhang, H., Marable, D., Catravas, J.D., Hill, W.D. and Webb, R.C. (2001) Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension, 37, 781-786.
  7. Uehara, Y., Numabe, A., Hirawa, N., Kawabata, Y., Iwai, J., Ono, H., Matsuoka, H., Takabatake, Y., Yagi, S. and Sugimoto, T. (1991) Antihypertensive effects of cicletanine and renal protection in Dahl salt-sensitive rats. J. Hypertens., 9, 719-728.
  8. Rajagopalan, S., Kurz, S., Munzel, T., Tarpey, M., Freeman, B.A., Griendling, K.K. and Harrison, D.G. (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J. Clin. Invest., 97, 1916-1923.
  9. Russo, C., Olivieri, O., Girelli, D., Faccini, G., Zenari, M.L., Lombardi, S. and Corrocher, R. (1998) Anti-oxidant status and lipid peroxidation in patients with essential hypertension. J. Hypertens., 16, 1267-1271.
  10. Ulker, S., McMaster, D., McKeown, P.P. and Bayraktutan, U. (2003) Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation. Cardiovasc. Res., 59, 488-500.
  11. Meng, S., Roberts, L.J., 2nd, Cason, G.W., Curry, T.S. and Manning, R.D., Jr. (2002) Superoxide dismutase and oxidative stress in Dahl salt-sensitive and -resistant rats. Am. J. Physiol. Regul. Integr. Comp. Physiol., 283, R732- R738.
  12. Lewis, P., Stefanovic, N., Pete, J., Calkin, A.C., Giunti, S., Thallas-Bonke, V., Jandeleit-Dahm, K.A., Allen, T.J., Kola, I., Cooper, M.E. and de Haan, J.B. (2007) Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation, 115, 2178-2187.
  13. Vera, T., Kelsen, S., Yanes, L.L., Reckelhoff, J.F. and Stec, D.E. (2007) HO-1 induction lowers blood pressure and superoxide production in the renal medulla of angiotensin II hypertensive mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., 292, R1472-R1478.
  14. Kang, K.T., Sullivan, J.C., Sasser, J.M., Imig, J.D. and Pollock, J.S. (2007) Novel nitric oxide synthase--dependent mechanism of vasorelaxation in small arteries from hypertensive rats. Hypertension, 49, 893-901.
  15. Kang, K.T., Sullivan, J.C., Spradley, F.T., d'Uscio, L.V., Katusic, Z.S. and Pollock, J.S. Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats. Am. J. Physiol. Heart. Circ. Physiol., 300, H718-H724.
  16. Inscho, E.W., Cook, A.K., Murzynowski, J.B. and Imig, J.D. (2004) Elevated arterial pressure impairs autoregulation independently of AT(1) receptor activation. J. Hypertens., 22, 811-818.
  17. Vanourkova, Z., Kramer, H.J., Huskova, Z., Vaneckova, I., Opocensky, M., Chabova, V.C., Tesar, V., Skaroupkova, P., Thumova, M., Dohnalova, M., Mullins, J.J. and Cervenka, L. (2006) AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension. J. Hypertens., 24, 2465-2472.
  18. Kase, H., Hashikabe, Y., Uchida, K., Nakanishi, N. and Hattori, Y. (2005) Supplementation with tetrahydrobiopterin prevents the cardiovascular effects of angiotensin II-induced oxidative and nitrosative stress. J. Hypertens., 23, 1375-1382.
  19. Landmesser, U., Dikalov, S., Price, S.R., McCann, L., Fukai, T., Holland, S.M., Mitch, W.E. and Harrison, D.G. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest., 111, 1201-1209.
  20. Pollock, D.M. and Rekito, A. (1998) Hypertensive response to chronic NO synthase inhibition is different in Sprague-Dawley rats from two suppliers. Am. J. Physiol., 275, R1719-R1723.
  21. Sullivan, J.C., Pollock, D.M. and Pollock, J.S. (2002) Altered nitric oxide synthase 3 distribution in mesenteric arteries of hypertensive rats. Hypertension, 39, 597-602.
  22. Schneider, M.P., Wach, P.F., Durley, M.K., Pollock, J.S. and Pollock, D.M. (2010) Sex differences in acute ANG II-mediated hemodynamic responses in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., 299, R899-R906.
  23. Sasser, J.M., Sullivan, J.C., Hobbs, J.L., Yamamoto, T., Pollock, D.M., Carmines, P.K. and Pollock, J.S. (2007) Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J. Am. Soc. Nephrol., 18, 143-154.
  24. Westman, G. and Marklund, S.L. (1980) Diethyldithiocarbamate, a superoxide dismutase inhibitor, decreases the radioresistance of Chinese hamster cells. Radiat. Res., 83, 303-311.
  25. Griendling, K.K., Sorescu, D. and Ushio-Fukai, M. (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res., 86, 494-501.
  26. Kim, M., Han, C.H. and Lee, M.Y. (2014) NADPH oxidase and the cardiovascular toxicity associated with smoking. Toxicol. Res., 30, 149-157.
  27. Griendling, K.K., Minieri, C.A., Ollerenshaw, J.D. and Alexander, R.W. (1994) Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res., 74, 1141-1148.
  28. Didion, S.P., Kinzenbaw, D.A. and Faraci, F.M. (2005) Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction. Hypertension, 46, 1147-1153.
  29. Fukui, T., Ishizaka, N., Rajagopalan, S., Laursen, J.B., Capers, Q., Taylor, W.R., Harrison, D.G., de Leon, H., Wilcox, J.N. and Griendling, K.K. (1997) p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ. Res., 80, 45-51.
  30. Kim, S.M. and Kang, J.H. (1997) Peroxidative activity of human Cu,Zn-superoxide dismutase. Mol. Cells, 7, 120-124.
  31. Gongora, M.C., Qin, Z., Laude, K., Kim, H.W., McCann, L., Folz, J.R., Dikalov, S., Fukai, T. and Harrison, D.G. (2006) Role of extracellular superoxide dismutase in hypertension. Hypertension, 48, 473-481.
  32. Zhan, C.D., Sindhu, R.K., Pang, J., Ehdaie, A. and Vaziri, N.D. (2004) Superoxide dismutase, catalase and glutathione peroxidase in the spontaneously hypertensive rat kidney: effect of antioxidant-rich diet. J. Hypertens., 22, 2025-2033.
  33. Welch, W.J., Chabrashvili, T., Solis, G., Chen, Y., Gill, P.S., Aslam, S., Wang, X., Ji, H., Sandberg, K., Jose, P. and Wilcox, C.S. (2006) Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response. Hypertension, 48, 934-941.
  34. Carlsson, L.M., Marklund, S.L. and Edlund, T. (1996) The rat extracellular superoxide dismutase dimer is converted to a tetramer by the exchange of a single amino acid. Proc. Natl. Acad. Sci. U.S.A., 93, 5219-5222.
  35. Karlsson, K. and Marklund, S.L. (1988) Extracellular superoxide dismutase in the vascular system of mammals. Biochem. J., 255, 223-228.
  36. Marklund, S.L. (1984) Extracellular superoxide dismutase and other superoxide dismutase isoenzymes in tissues from nine mammalian species. Biochem. J., 222, 649-655.
  37. Jung, O., Marklund, S.L., Geiger, H., Pedrazzini, T., Busse, R. and Brandes, R.P. (2003) Extracellular superoxide dismutase is a major determinant of nitric oxide bioavailability: in vivo and ex vivo evidence from ecSOD-deficient mice. Circ. Res., 93, 622-629.
  38. Fukai, T., Siegfried, M.R., Ushio-Fukai, M., Griendling, K.K. and Harrison, D.G. (1999) Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ. Res., 85, 23-28.
  39. Daiber, A., Mulsch, A., Hink, U., Mollnau, H., Warnholtz, A., Oelze, M. and Munzel, T. (2005) The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine. Am. J. Cardiol., 96, 25i-36i.