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.
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Research Article|
May 22 2013
Decreased Nox4 levels in the myocardium of patients with aortic valve stenosis
María U. Moreno;
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
Correspondence: Dr Maria U. Moreno (email mumoreno@unav.es) or email Dr Guillermo Zalba (email gzalba@unav.es).
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Idoia Gallego;
Idoia Gallego
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
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Begoña López;
Begoña López
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
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Arantxa González;
Arantxa González
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
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Ana Fortuño;
Ana Fortuño
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
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Gorka San José;
Gorka San José
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
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Félix Valencia;
Félix Valencia
†Division of Cardiology, Vírgen de la Victoria University Hospital, Campus Universitario de Teatinos, s/n. 29010 Málaga, Spain
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Juan José Gómez-Doblas;
Juan José Gómez-Doblas
†Division of Cardiology, Vírgen de la Victoria University Hospital, Campus Universitario de Teatinos, s/n. 29010 Málaga, Spain
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Eduardo de Teresa;
Eduardo de Teresa
†Division of Cardiology, Vírgen de la Victoria University Hospital, Campus Universitario de Teatinos, s/n. 29010 Málaga, Spain
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Ajay M. Shah;
Ajay M. Shah
‡Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, Denmark Hill Campus, 125 Coldharbour Lane, London SE5 9NU, U.K.
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Javier Díez;
Javier Díez
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
§Department of Cardiology and Cardiac Surgery, University Clinic, University of Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain
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Guillermo Zalba
*Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain
Correspondence: Dr Maria U. Moreno (email mumoreno@unav.es) or email Dr Guillermo Zalba (email gzalba@unav.es).
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Clin Sci (Lond) (2013) 125 (6): 291–300.
Article history
Received:
November 13 2012
Revision Received:
March 27 2013
Accepted:
April 04 2013
Accepted Manuscript online:
April 04 2013
Citation
María U. Moreno, Idoia Gallego, Begoña López, Arantxa González, Ana Fortuño, Gorka San José, Félix Valencia, Juan José Gómez-Doblas, Eduardo de Teresa, Ajay M. Shah, Javier Díez, Guillermo Zalba; Decreased Nox4 levels in the myocardium of patients with aortic valve stenosis. Clin Sci (Lond) 1 September 2013; 125 (6): 291–300. doi: https://doi.org/10.1042/CS20120612
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