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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 47; no. 1; pp. 81 - 86
• Main Authors: Zhou, Ming-Sheng, Schulman, Ivonne Hernandez, Pagano, Patrick J, Jaimes, Edgar A, Raij, Leopoldo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.01.2006; Hagerstown, MD Lippincott
• Subjects: Acetylcholine - pharmacology; Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Aorta - drug effects; Aorta - metabolism; Arterial hypertension. Arterial hypotension; Atherosclerosis - etiology; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Chemokine CCL2 - genetics; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Dose-Response Relationship, Drug; Endocrine kidney. Renin-angiotensin-aldosterone system; Endothelium, Vascular - physiopathology; Fundamental and applied biological sciences. Psychology; Hypertension - blood; Hypertension - enzymology; Hypertension - metabolism; Hypertension - physiopathology; Hypertrophy, Left Ventricular - chemically induced; In Vitro Techniques; Medical sciences; Membrane Glycoproteins - deficiency; Mice; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases - deficiency; NADPH Oxidases - metabolism; Osmolar Concentration; Rats; Rats, Inbred Dahl; Renin - blood; RNA, Messenger - metabolism; Scavenger Receptors, Class E - genetics; Sodium Chloride, Dietary - administration & dosage; Sodium Chloride, Dietary - pharmacology; Systole; Vasoconstrictor Agents - metabolism; Vasoconstrictor Agents - pharmacology; Vasodilation; Vasodilator Agents - pharmacology; Vertebrates: endocrinology; Systolic pressure; Rat; Body weight; Peptide hormone; Oxidase; Cardiovascular disease; Free radical; Vascular disease; Octapeptide; Renin; Atherosclerotic plaque; Atherosclerosis; Aorta; Arterial pressure; Aspartic endopeptidases; Blood pressure; Angiotensin II; Human; Hypertension; Oxygen; free radicals; Urinary system disease; Enzyme; Rodentia; Left ventricle; Endothelium; Peptidases; Adventitia; Vertebrata; Hyperoxides; Mammalia; Treatment; Sodium; Animal; Nitric oxide; Hydrolases; Oxidoreductases; Proteinuria
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000197182.65554.c7

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, 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. 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 with gp91 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.