Abstract
Increased expression of matrix metalloproteinase-1 (MMP-1) has been observed in the lesions of atherosclerosis and aneurysms; however, it is not fully understood whether macrophage-derived MMP-1 affects these diseases. To investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases, we generated transgenic (Tg) rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/promoter. Tg rabbits exhibited no visible abnormalities throughout their bodies. Western blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg rabbits. For the first experiment, Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks, and aortic and coronary atherosclerosis were evaluated. The gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits, but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic examination. For the second experiment, we generated aortic aneurysms by incubating with elastase. Compared with non-Tg rabbits, Tg rabbits exhibited a significantly greater aortic dilation. Increased macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and aneurysms. These results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.
Highlights
The accumulation of macrophage-derived foam cells in the intima of large arteries is a hallmark of human and experimental animal atherosclerosis[1– 3]
We generated Tg rabbits expressing human matrix metalloproteinase-1 (MMP-1) in the macrophage lineage to investigate whether increased matrix metalloproteinases (MMPs)-1 affects atherosclerosis and aortic aneurysm formation in cholesterol-fed rabbits
These results suggest that MMP-1 is not involved in the macrophage accumulation in the lesions even though MMP-1 can disrupt the elastic lamina
Summary
The accumulation of macrophage-derived foam cells in the intima of large arteries is a hallmark of human and experimental animal atherosclerosis[1– 3]. These macrophages play an important role in the development of atherosclerosis and its complications because they secrete a variety of bio-reactive substances such as cytokines, matrix metalloproteinases (MMPs), pro-coagulant protein tissue factor, and reactive oxygen species. These substances, either singly or collaboratively, function in the lesion progression[2,4]. One was MMP-1, known as interstitial collagenase, which is highly expressed by lesional macrophages[13]
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