A Role of Matrix Metalloproteinase-8 in Atherosclerosis

• Published in: Circulation research Vol. 105; no. 9; pp. 921 - 929
• Main Authors: Laxton, Ross C, Hu, Yanhua, Duchene, Johan, Zhang, Feng, Zhang, Zhongyi, Leung, Kit-Yi, Xiao, Qingzhong, Scotland, Ramona S, Hodgkinson, Conrad P, Smith, Katherine, Willeit, Johann, López-Otín, Carlos, Simpson, Iain A, Kiechl, Stefan, Ahluwalia, Amrita, Xu, Qingbo, Ye, Shu
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 23.10.2009; Lippincott Williams & Wilkins
• Subjects: Angiotensin II - metabolism; Animals; Aortic Diseases - enzymology; Aortic Diseases - genetics; Aortic Diseases - physiopathology; Aortic Diseases - prevention & control; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - physiopathology; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure; Cardiology. Vascular system; Carotid Artery Diseases - enzymology; Carotid Artery Diseases - genetics; Carotid Artery Diseases - prevention & control; Collagen - metabolism; Coronary Stenosis - enzymology; Coronary Stenosis - genetics; Coronary Stenosis - prevention & control; Disease Models, Animal; Disease Progression; Endothelium, Vascular - metabolism; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Predisposition to Disease; Humans; Leukocyte Rolling; Macrophages - metabolism; Male; Matrix Metalloproteinase 8 - deficiency; Matrix Metalloproteinase 8 - genetics; Matrix Metalloproteinase 8 - metabolism; Medical sciences; Mice; Mice, Knockout; Polymorphism, Single Nucleotide; Prospective Studies; Severity of Illness Index; Vascular Cell Adhesion Molecule-1 - metabolism; Vertebrates: cardiovascular system; Vascular disease; Peptidases; Vertebrata; Mammalia; Gene; Enzyme; Atherosclerosis; Hydrolases; Cardiovascular disease; Metalloendopeptidases; matrix metalloproteinase; Circulatory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.200279

RATIONALE:Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I. OBJECTIVE:We studied whether MMP8 plays a role in atherogenesis. METHODS AND RESULTS:In atherosclerosis-prone apolipoprotein E–deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8-deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing that Ang I cleavage by MMP8 generated Ang II, MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule (VCAM)-1 expression and that MMP8-deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship among MMP8 gene variation, plasma VCAM-1 level, and atherosclerosis progression was also observed in a population-based, prospective study. CONCLUSIONS:These results indicate that MMP8 is an important player in atherosclerosis.