title: Decreased Nox4 levels in the myocardium of patients with aortic valve stenosis.
abstract: The NADPH oxidases are a key family of ROS (reactive oxygen species)-producing enzymes which may differentially contribute to cardiac pathophysiology. Animal studies show uncertain results regarding the regulation of cardiac Nox4 by pressure overload and no data are available on human myocardial Nox4. In the present study, we evaluated Nox4 expression and its relationship with myocardial remodelling and LV (left ventricular) function in patients with severe AS (aortic valve stenosis). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. LV morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-CVDs (cardiovascular diseases) were analysed as controls. Nox4 localization was evaluated by immunohistochemistry and quantified by Western blot. Myocardial capillary density, fibrosis and cardiomyocyte dimensions and apoptosis were assessed histologically to evaluate myocardial remodelling. Nox4 was present in samples from all subjects and expressed in cardiomyocytes, VSMCs (vascular smooth muscle cells), endothelium and fibroblasts. Nox4 levels were reduced 5-fold in AS patients compared with controls (P<0.01). Nox4 levels directly correlated with cardiomyocyte cross-sectional area (r=0.299, P<0.05) and diameter (r=0.406, P<0.05) and capillary density (r=0.389, P<0.05), and inversely with cardiomyocyte apoptosis (r=-0.316, P<0.05) in AS patients. In addition, Nox4 levels correlated with echocardiographic parameters (LV ejection fraction: r=0.353, P<0.05; midwall fractional shortening: r=0.355, P<0.05; deceleration time: r=-0.345, P<0.05) in AS patients. Nox4 is expressed in human myocardium and reduced in AS patients. The observed associations of Nox4 with cardiomyocyte parameters and capillary density in AS patients suggest a potential role of Nox4 deficiency in the myocardial remodelling present in the human pressure-overloaded heart.
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain. mumoreno@unav.es
authors.forename: María U
authors.initials: MU
authors.lastname: Moreno
authors.forename: Idoia
authors.initials: I
authors.lastname: Gallego
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.forename: Ana
authors.initials: A
authors.lastname: Fortuño
authors.forename: Gorka
authors.initials: G
authors.lastname: San José
authors.forename: Félix
authors.initials: F
authors.lastname: Valencia
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Gómez-Doblas
authors.forename: Eduardo
authors.initials: E
authors.lastname: de Teresa
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Guillermo
authors.initials: G
authors.lastname: Zalba
mesh_terms: D000328:Adult; D000368:Aged; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology; D017209:Apoptosis; D001706:Biopsy; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D015536:Down-Regulation; D018619:Echocardiography, Doppler, Pulsed; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000032:analysis*; D009687:Nuclear Proteins / Q000032:analysis; D012720:Severity of Illness Index; D013318:Stroke Volume; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D009687:Nuclear Proteins; C473592:POLDIP2 protein, human; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human