HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Temporal and quantitative analysis of expression of metalloproteinases (MMPs) and their endogenous inhibitors in atherosclerotic lesions

Ying Yu1, Tomonari Koike1, Shuji Kitajima2, Enqi Liu2, Masatoshi Morimoto3, Masashi Shiomi4, Kinta Hatakeyama5, Yujiro Asada5, Ke-Yong Wang6, Yasuyuki Sasaguri6, Teruo Watanabe7 and Jianglin Fan1

1Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan, 2Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan, 3Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan, 4Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Japan, 5The First Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan, 6Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan and 7Fukuoka Wajiro Hospital, Fukuoka, Japan.

Offprint requests to: Jianglin Fan, Chairman and Professor, Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-City, Yamanashi 409-3898, Japan. e-mail: fan_molpatho@yahoo.co.jp


Summary. Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of vascular diseases, such as atherosclerosis, plaque rupture and aneurysms. Although several MMPs have been demonstrated in the lesions of atherosclerosis, their expression profiles during the initiation and progression of lesions have not been fully determined. We hypothesized that the expression of various MMPs, along with their endogenous inhibitors, may be differentially regulated dependent upon the lesion progression. Therefore, we made a temporal and quantitative analysis of the mRNA and protein expression of MMPs and tissue inhibitors of metalloproteinases expressed in the different stages of atherosclerotic lesions of rabbits and humans. We found that MMP-1, MMP-12 and MMP-13 expression was nearly absent in the normal arterial wall, but was remarkably increased with lesion progression. Furthermore, the expression of these MMPs in the lesions was closely associated with intimal macrophages and monocyte chemoattractant protein-1 expression, suggesting that the intimal macrophages are the major source of production of these MMPs. MMP-3 and MT1-MMP were also significantly upregulated in the early-stage lesions and fatty streaks compared to the normal aortas of rabbits. Our results indicate that MMP-1, -12, and -13 derived from intimal macrophages may play a pivotal role in both lesion initiation and progression, and therefore are potential therapeutic targets for the treatment of plaque rupture and aneurysm formation. Histol Histopathol 23, 1503-1516 (2008)

Key words: MMPs, Atherosclerosis, Plaque stability, matrix degradation, macrophages

DOI: 10.14670/HH-23.1503