title: Relationship between NOX4 level and angiotensin II signaling in Gitelman's syndrome. Implications with hypertension.
abstract: Recent evidence showed that endogenous nicotinamide adenine dinucleotide phosphate-oxidase 4 (NOX4) may exert a protective role on the cardiovascular system inducing vasodilation, reduction of blood pressure, and anti-proliferative actions. However, the functional significance of NOX4 in the cardiovascular system in humans remains elusive. Mononuclear cell levels of NOX4 were assessed by immunoblotting in 14 Gitelman's patients (GS), a unique human model of endogenous Ang II signaling antagonism and activation of anti-atherosclerotic and anti-remodeling defenses, and compared to 11 untreated essential hypertensive patients as well as to 11 healthy normotensive subjects. The association between NOX4 and its effector heme oxygenase (HO-1) (sandwich immunoassay) was also evaluated. NOX4 protein levels were decreased in hypertensive patients as compared to both GS and healthy subjects (1.06±0.31 AU vs. 1.76±0.54, P=0.002 and vs. 1.61±0.54, P=0.018, respectively). NOX4 protein level did not differ between GS and healthy subjects. HO-1 levels were increased in GS patients as compared to both hypertensive patients and healthy subjects (8.65±3.08 ng/ml vs 3.70±1.19, P<0.0001, and vs 5.49±1.04, P=0.008, respectively. NOX4 levels correlate with HO-1 levels only in GS (r(2)=0.63; P=0.001), (r(2)=0.088; P=ns, in hypertensive patients and r(2)=0.082; P=ns, in healthy subjects). Our findings show that NOX4 and its effector HO-1 are reduced in hypertensive patients compared to GS patients, a human model opposite to hypertension. Although the functional significance of NOX4 needs further clarification, our preliminary data in a unique human model of anti-atherosclerotic and anti-remodeling defenses activation, highlight the potentially protective role of NOX4 in the human cardiovascular system.
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
authors.affiliation: Department Clinical and Molecular Medicine, Division of Cardiology, Sant'Andrea Hospital, 'Sapienza' University of Rome Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Savoia
authors.affiliation: Department of Nutrition, University of California Davis, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davis
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Ravarotto
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maiolino
keywords: Angiotensin II signaling; Gitelman’s syndrome; NOX4; cardiovascular remodeling; hypertension