Phagocytic NADPH Oxidase-Dependent Superoxide Production Stimulates Matrix Metalloproteinase-9: Implications for Human Atherosclerosis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 3; pp. 587 - 593
• Main Authors: Zalba, Guillermo, Fortuño, Ana, Orbe, Josune, San José, Gorka, Moreno, María U., Belzunce, Miriam, Rodríguez, José Antonio, Beloqui, Oscar, Páramo, José Antonio, Díez, Javier
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2007; Hagerstown, MD Lippincott
• Subjects: Adult; Analysis of Variance; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Carotid Artery Diseases - enzymology; Carotid Artery Diseases - physiopathology; Carotid Artery, Common - enzymology; Carotid Artery, Common - pathology; Case-Control Studies; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme-Linked Immunosorbent Assay; Humans; Leukocytes, Mononuclear - enzymology; Male; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Middle Aged; Multivariate Analysis; NADPH Oxidases - metabolism; Orthopedic surgery; Oxidative Stress - physiology; Oxygen - metabolism; Phagocytes - enzymology; Pharmacology. Drug treatments; Probability; Sensitivity and Specificity; Superoxides - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Vasodilator agents. Cerebral vasodilators; Human; Enzyme; Metalloendopeptidases; Cardiovascular disease; Gelatinase B; NAD(P)H oxidase; Vascular disease; Peptidases; MMP; Hyperoxides; NADPH oxidase; Atherosclerosis; Hydrolases; superoxide
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/01.ATV.0000256467.25384.c6

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.