Published Online
on December 12, 2005

A more recent version of this article appeared on January 1, 2006

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Submitted on July 12, 2005
Revised on July 27, 2005

Reduced NAD(P)H Oxidase in Low Renin Hypertension Link Among Angiotensin II, Atherogenesis, and Blood Pressure

Ming-Sheng Zhou; Ivonne Hernandez Schulman; Patrick J. Pagano; Edgar A. Jaimes; and Leopoldo Raij^*

From the Nephrology and Hypertension Section (M.-S.Z., I.H.S., E.A.J., L.R.), Veterans Affairs Medical Center and Division of Nephrology and Hypertension and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Fla; and Hypertension and Vascular Research Division (P.J.P.), Henry Ford Hospital, Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: LRaij{at}med.miami.edu.

Abstract--Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91^phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91^phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47^phox with gp91^phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168±5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159±5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.

Key words: endothelium • sodium • hypertension • free radicals • atherosclerosis

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