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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:587.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Phagocytic NADPH Oxidase-Dependent Superoxide Production Stimulates Matrix Metalloproteinase-9

Implications for Human Atherosclerosis

Guillermo Zalba; Ana Fortuño; Josune Orbe; Gorka San José; María U. Moreno; Miriam Belzunce; José Antonio Rodríguez; Oscar Beloqui; José Antonio Páramo; Javier Díez

From Division of Cardiovascular Sciences (G.Z., A.F., J.O., G.S.J., M.U.M., M.B., J.A.R., J.A.P., J.D.), Centre for Applied Medical Research; Department of Internal Medicine (O.B.), Division of Hematology (A.P.), Department of Cardiology and Cardiovascular Surgery (J.D.), University Clinic, School of Medicine, University of Navarra, Pamplona, Spain.

Correspondence to Dr Guillermo Zalba, Área de Ciencias Cardiovasculares. Centro de Investigación Médica Aplicada. Avda. Pío XII 55, 31008 Pamplona, Spain. E-mail gzalba{at}unav.es

Objective— Data suggest that matrix metalloproteinase-9 (MMP-9) has a role in atherosclerosis. The phagocytic NADPH oxidase has been also associated with atherosclerosis. This study aimed to investigate the association between phagocytic NADPH oxidase and MMP-9 in human atherosclerosis.

Methods and Results— In vitro experiments performed in human monocytes showed that NADPH oxidase activation enhanced MMP-9 secretion and activity, determined by enzyme-linked immunosorbent assay and zymography, respectively. Immunohistochemical study showed that phagocytic NADPH oxidase localized with MMP-9 in endarterectomies from patients with carotid stenosis. In addition, a positive relationship (P<0.001) was found between phagocytic NADPH oxidase-dependent superoxide production determined with lucigenin and plasma MMP-9 levels in 188 asymptomatic subjects free of overt clinical atherosclerosis. In multivariate analysis, this association remained significant after adjustment for cardiovascular risk factors. Interestingly, subjects in the upper quartile of superoxide production exhibited the highest values of MMP-9, oxidized low-density lipoprotein, nitrotyrosine, carotid intima media thickness, and an increased presence of carotid plaques.

Conclusions— Enhanced NADPH oxidase-dependent ·O₂^– production stimulates MMP-9 in monocytes and this relationship may be relevant in the atherosclerotic process. Moreover, MMP-9 emerges as an important mediator of the phagocytic NADPH oxidase-dependent oxidative stress in atherosclerosis.

Enhanced ·O₂^– production increased MMP-9 activation in monocytes. NADPH oxidase and MMP-9 colocalized in atherosclerotic plaques. Enhanced NADPH oxidase-dependent ·O₂^– production associated with enhanced plasma MMP-9 levels in asymptomatic individuals. Interestingly, subjects in the upper quartile of ·O₂^– production associated with subclinical carotid atherosclerosis.

Key Words: atherosclerosis • NADPH oxidase • superoxide • MMP

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