Novel Competitive Inhibitor of NAD(P)H Oxidase Assembly Attenuates Vascular O 2 − and Systolic Blood Pressure in Mice

Circulation Research - Tập 89 Số 5 - Trang 408-414 - 2001
Federico E. Rey1,2, Eugenia Cifuentes-Pagano1,2, Arash Kiarash1,2, Mark T. Quinn1,2, Patrick J. Pagano1,2
1From the Hypertension and Vascular Research Division (F.E.R., M.E.C., A.K., P.J.P.), Henry Ford Hospital, Detroit, Mich; and Veterinary Molecular Biology Laboratory (M.T.Q.), Montana State University, Bozeman, Mont.
2Veterinary Molecular Biology Laboratory (M.T.Q.), Montana State University, Bozeman, Mont.

Tóm tắt

We previously reported enhanced expression of the p67 phox and gp91 phox components of NAD(P)H oxidase in angiotensin (Ang) II–induced hypertension, suggesting de novo assembly in response to Ang II. To examine the direct involvement of NAD(P)H oxidases in Ang II–induced O 2 − production, we designed a chimeric peptide that inhibits p47 phox association with gp91 phox in NAD(P)H oxidase (gp91ds- tat ). This was achieved by linking a 9-amino acid peptide (aa) derived from HIV-coat protein ( tat ) to a 9-aa sequence of gp91 phox (known to interact with p47 phox ). As a control, we constructed a chimera containing tat and a scrambled gp91 sequence (scramb- tat ). We found that gp91ds- tat decreased O 2 − levels in aortic rings treated with Ang II (10 pmol/L) but had no effect on either the O 2 − -generating enzyme xanthine oxidase or potassium superoxide–generated O 2 − . We infused vehicle, Ang II (0.75 mg · kg −1 · d −1 ), Ang II+gp91ds- tat (10 mg · kg −1 · d −1 ), or Ang II+scramb- tat intraperitoneally in C57Bl/6 mice and measured systolic blood pressure (SBP) on days 0, 3, 5, and 7 of infusion. SBP increased by day 3 in mice given Ang II and Ang II+scramb- tat but was significantly lower with Ang II+gp91- tat . On day 7, SBP was still significantly inhibited in mice given Ang II+gp91ds- tat , whereas Ang II–induced O 2 − production was inhibited throughout the aorta as detected by dihydroethidium staining, consistent with the ability of this inhibitor to block the various vascular NAD(P)H oxidase isoforms. These data support the hypothesis that inhibition of the interaction of p47 phox and gp91 phox (or its homologues) can block O 2 − production and attenuate blood pressure elevation in mice.

Từ khóa


Tài liệu tham khảo

10.1161/01.RES.69.3.601

10.1152/ajpheart.1986.250.5.H822

10.1152/ajpcell.1991.260.2.C219

10.1038/320454a0

Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol. 1992; 263: H321–H326.

Katusic ZS, Vanhoutte PM. Superoxide anion is an endothelium-derived contracting factor. Am J Physiol. 1989; 257: H33–H37.

10.1161/hyp.34.6.1247

10.1172/JCI118623

10.1161/hyp.33.5.1225

10.1161/res.82.7.810

10.1161/circ.95.3.588

10.1152/ajpheart.2000.279.5.H2234

Mohazzab-H KM, Wolin MS. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol. 1994; 267: L815–L822.

Pagano PJ, Ito Y, Tornheim K, Gallop PM, Tauber AI, Cohen RA. An NADPH oxidase superoxide-generating system in the rabbit aorta. Am J Physiol. 1995; 268: H2274–H2280.

10.1161/res.80.1.45

10.1161/hyp.32.2.331

10.3109/10715769309056499

10.1016/S0008-6363(98)00003-0

10.1161/res.74.6.8187280

10.1074/jbc.273.16.9539

Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RAK, Macharzina R, Bräsen JH, Meinertz T, Münzel T. Increased NAD (P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int. 1999; 56: 252–260.

10.3109/10623329909165308

10.1074/jbc.274.28.19814

10.1161/res.87.12.1195

10.1038/43459

10.1073/pnas.130135897

10.1016/S0968-0004(00)01658-3

10.1002/jlb.60.6.677

10.1073/pnas.92.15.7110

10.1182/blood.V87.5.2005.2005

10.1161/res.88.9.888

10.1073/pnas.91.2.664

10.4049/jimmunol.159.4.1666

10.1161/res.82.12.1298

10.1016/0022-1759(96)00144-5

10.1016/0378-4274(86)90147-5

10.1111/j.1432-1033.1992.tb17159.x

10.1096/fasebj.5.1.1703974

10.1073/pnas.94.26.14483

Jones SA, O’Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OTG. Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol. 1996; 271: H1626–H1634.

10.1161/circ.101.11.1234

10.1152/ajpheart.1999.277.3.H1007

10.1165/ajrcmb.11.1.8018341

Klebanoff SJ. Myeloperoxidase. Proc Assoc Am Physicians. 2001; 111: 383–389.

10.1161/res.86.5.494

10.1086/513849

10.1182/blood.V78.7.1834.1834

10.1083/jcb.131.3.775

Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000; 52: 11–34.

Simon G Abraham G. Angiotensin II administration as an experimental model of hypertension. In: Laragh JH Brenner BM eds. Hypertension: Pathophysiology Diagnosis and Management. New York NY: Raven Press; 1995: 1423–1435.

10.1016/S0008-6363(00)00091-2

10.1161/circ.99.15.2027

Thông tin
Thông tin xuất bản

Circulation Research

Tập 89 Số 5

408-414

Thông tin tác giả