Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits

• Published in: Circulation (New York, N.Y.) Vol. 113; no. 16; pp. 1993 - 2001
• Main Authors: JINGYAN LIANG, LIU, Enqi, SASAGURI, Yasuyuki, WATANABE, Shigeyuki, JIANGLIN FAN, YING YU, KITAJIMA, Shuji, KOIKE, Tomonari, YINGJI JIN, MORIMOTO, Masatoshi, HATAKEYAMA, Kinta, ASADA, Yujiro, WATANABE, Teruo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 25.04.2006
• Subjects: Animals; Animals, Genetically Modified; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Movement; Coronary Artery Disease - enzymology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Humans; Immunohistochemistry; Macrophages - physiology; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9 - analysis; Matrix Metalloproteinases - analysis; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Metalloendopeptidases - analysis; Metalloendopeptidases - physiology; Muscle, Smooth, Vascular - pathology; Neurology; Rabbits; Vascular diseases and vascular malformations of the nervous system; Enzyme; Rabbit; Macrophage elastase; metalloproteinases; Metalloendopeptidases; Cardiovascular disease; Inflammation; Lagomorpha; Vascular disease; Peptidases; Vertebrata; Mammalia; genetically modified; Animal; Atherosclerosis; Hydrolases; animals
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.105.596031

Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined. We compared the susceptibility of MMP-12 transgenic (Tg) rabbits to cholesterol-rich diet-induced atherosclerosis with that of non-Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did non-Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-3, suggesting that MMP-12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis. Overexpression of MMP-12 causes accelerated atherosclerosis in Tg rabbits. These results suggest that macrophage-derived MMP-12 participates in the progression of atherosclerosis.