Abstract
Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.
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Taniyama Y, Griendling KK : Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension 2003; 42: 1075–1081.
Van Heerebeek L, Meischl C, Stooker W, Meijer CJ, Niessen HW, Roos D : NADPH oxidase(s): new source(s) of reactive oxygen species in the vascular system? J Clin Pathol 2002; 55: 561–568.
Lassegue B, Clempus RE : Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003; 285: R277–R297.
Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark SM, Callis GM, Quinn MT : Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci U S A 1997; 94: 14483–14488.
Mollnau H, Wendt M, Szocs K, et al: Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 2002; 90: E58–E65.
Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF : Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 2001; 37: 529–534.
Zalba G, Beaumont FJ, San Jose G, et al: Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000; 35: 1055–1061.
Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG : Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 2004; 35: 584–589.
Hamilton CA, Brosnan MJ, Al-Benna S, Berg G, Dominiczak AF : NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. Hypertension 2002; 40: 755–762.
Szocs K, Lassegue B, Sorescu D, et al: Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol 2002; 22: 21–27.
Lassegue B, Sorescu D, Szocs K, et al: Novel gp91(phox) homologues in vascular smooth muscle cells: Nox1 mediates angiotensin II–induced superoxide formation and redox-sensitive signaling pathways. Circ Res 2001; 88: 888–894.
Touyz RM, Chen X, Tabet F, et al: Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 2002; 90: 1205–1213.
Wingler K, Wunsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH : Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Free Radic Biol Med 2001; 31: 1456–1464.
Fukui T, Ishizaka N, Rajagopalan S, et al: p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res 1997; 80: 45–51.
Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK : Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 2002; 91: 406–413.
Touyz RM, Schiffrin EL : Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D–dependent NAD(P)H oxidase-sensitive pathways. J Hypertens 2001; 19: 1245–1254.
Grote K, Flach I, Luchtefeld M, Akin E, et al: Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase–derived reactive oxygen species. Circ Res 2003 13; 92: e80–e86.
Zou Y, Akazawa H, Qin Y, et al: Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 2004; 6: 499–506.
Umemoto S, Tanaka M, Kawahara s, et al: Cralcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dimutase in stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 877–885.
Tanaka M, Umemoto S, Kawahara S, et al: Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats. Hypertens Res 2005; 28: 67–77.
Takai S, Kirimura K, Jin D, et al: Significance of angiotensin II receptor blocker lipophilicities and their protective effect against vascular remodeling. Hypertens Res 2005; 28: 593–600.
Moe KT, Aulia S, Jiang F, et al: Differential upregulation of Nox homologues of NADPH oxidase by tumor necrosis factor-alpha in human aortic smooth muscle and embryonic kidney cells. J Cell Mol Med 2006; 10: 231–239.
Kuroda J, Nakagawa K, Yamasaki T, et al: The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells 2005; 10: 1139–1151.
Suh YA, Arnold RS, Lassegue B, et al: Cell transformation by the superoxide-generating oxidase Mox1. Nature 1999; 401: 79–82.
Geiszt M, Kopp JB, Varnai P, Leto TL : Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A 2000; 97: 8010–8014.
Su B, Mitra S, Gregg H, et al: Redox regulation of vascular smooth muscle cell differentiation. Circ Res 2001; 8: 39–46.
Shiose A, Kuroda J, Tsuruya K, et al: A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem 2001; 276: 1417–1423.
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Akasaki, T., Ohya, Y., Kuroda, J. et al. Increased Expression of gp91phox Homologues of NAD(P)H Oxidase in the Aortic Media during Chronic Hypertension: Involvement of the Renin-Angiotensin System. Hypertens Res 29, 813–820 (2006). https://doi.org/10.1291/hypres.29.813
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DOI: https://doi.org/10.1291/hypres.29.813
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