Matrix Metalloproteinase 12 Accelerates the Initiation of Atherosclerosis and Stimulates the Progression of Fatty Streaks to Fibrous Plaques in Transgenic Rabbits

Abstract

Whether fatty streaks are directly followed by fibrous plaque formation in atherosclerosis remains controversial. Disruption of the basement membrane and elastic layers is thought to be essential for this process. Matrix metalloproteinase 12 (MMP-12) can degrade a broad spectrum of substrates, but the role of MMP-12 in the early stage of atherosclerosis is unclear. To investigate MMP-12 function in the initiation and progression of atherosclerosis, we investigated macrophage migration and elastolysis in relation to fatty streaks in human MMP-12 transgenic (hMMP-12 Tg) rabbits. Fatty streaks in hMMP-12 Tg rabbits fed a 1% cholesterol diet for 6 weeks (cholesterol-induced model of atherosclerosis) were more pronounced and were associated with more significant degradation of the internal elastic layer compared with wild-type (WT) animals. Numbers of infiltrating macrophages and smooth muscle cells in the lesions were increased in hMMP-12 Tg compared with WT animals. In both cuff- and ligation-induced models of atherosclerosis, smooth muscle cell-predominant atherosclerotic lesions were elevated with significant elastolysis of the internal elastic lamina in Tg compared with WT animals; "microelastolytic sites" were recognized before formation of the neointima in the cuff model only. These results indicate that MMP-12 may be critical to the initiation and progression of atherosclerosis via degradation of the elastic layers and/or basement membrane. Therefore, a specific MMP-12 inhibitor might prove useful for the treatment of progressive atherosclerosis.

MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr-/-Apob100/100 mouse

“…mmP-12, a macrophage elastase, was constitutively expressed during development. yamada et al have showed that mmP-12 transgenic rabbits accelerated the initiation of atherosclerosis and stimulated the progression of fatty streaks to fibrous plaques (19). johnson et al have reported that brachiocephalic artery plaques were significantly larger in ApoE/MMP-3 and ApoE/MMP-9 double knockouts compared to controls.…”

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…Since MMP-12 is not only involved in lung tissue remodeling-associated diseases [35,37,41,46,50,[81][82][83][84][85][86][87][88][89], substantial efforts have been made to develop MMP-12 synthetic inhibitors. However, inhibiting a specific MMP is a difficult goal because of the high conservation between many MMPs in terms of overall 3D-structure, topology of the catalytic domain and requirement of specific amino-acid residues in the active site [90,91].…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Recently, Yamada and coworkers have investigated macrophage migration and elastolysis in relation to fatty streaks in human MMP-12 transgenic (hMMP-12 Tg) rabbits, finding that MMP-12 production by macrophages plays a role in the transition from fatty acids to fibrous plaques during the progression of atherosclerosis (Yamada et al, 2008). On the basis of these results a specific MMP-12 inhibitor might eventually turn out to be useful for the treatment of progressive atherosclerosis.…”