Abstract
Matrix metalloproteinase‐9 (MMP‐9), or gelatinase B, has been hypothesized to be involved in the progression of atherosclerosis. In the arterial wall, accumulated macrophages secrete considerable amounts of MMP‐9 but its pathophysiological functions in atherosclerosis have not been fully elucidated. To examine the hypothesis that macrophage‐derived MMP‐9 may affect atherosclerosis, we created MMP‐9 transgenic (Tg) rabbits to overexpress the rabbit MMP‐9 gene under the control of the scavenger receptor A enhancer/promoter and examined their susceptibility to cholesterol diet‐induced atherosclerosis. Tg rabbits along with non‐Tg rabbits were fed a cholesterol diet for 16 and 28 weeks, and their aortic and coronary atherosclerosis was compared. Gross aortic lesion areas were significantly increased in female Tg rabbits at 28 weeks; however, pathological examination revealed that all the lesions of Tg rabbits fed a cholesterol diet for either 16 or 28 weeks were characterized by increased monocyte/macrophage accumulation and prominent lipid core formation compared with those of non‐Tg rabbits. Macrophages isolated from Tg rabbits exhibited higher infiltrative activity towards a chemoattractant, MCP‐1 in vitro and augmented capability of hydrolysing extracellular matrix in granulomatous tissue. Surprisingly, the lesions of Tg rabbits showed more advanced lesions with remarkable calcification in both aortas and coronary arteries. In conclusion, macrophage‐derived MMP‐9 facilitates the infiltration of monocyte/macrophages into the lesions thereby enhancing the progression of atherosclerosis. Increased accumulation of lesional macrophages may promote vascular calcification.
Highlights
Matrix metalloproteinases (MMPs), first described in 1962,1 are a family of zinc-dependent endopeptidases with more than 23 kinds reported in humans.[2]
Histological examinations revealed that the lesions of aortic atherosclerosis in Tg and non-Tg rabbits were predominantly composed of type II lesions, which were characterized by foam cell accumulation intermingled with small numbers of smooth muscle cells and extracellular matrix (ECM); the number of lesional macrophages was significantly increased by 2.8-fold in male (Figure 2) and 1.3fold in female Tg rabbits (Figure S3)
Accumulation of macrophage-derived foam cells in the intima of large arteries is a hallmark of atherosclerosis
Summary
Matrix metalloproteinases (MMPs), first described in 1962,1 are a family of zinc-dependent endopeptidases with more than 23 kinds reported in humans.[2]. MMP-9 deficiency protected against cholesterol diet-induced atherosclerosis,[28] but in another, MMP-9 inactivation increased the atherosclerotic plaque growth and progression.[29] In addition, a report indicated that overexpressing human MMP-9 in macrophages increased collagen content in lesions but showed no effects on atherosclerotic lesions in apoE KO mice.[30] Recently, we performed an RNAseq analysis of the aortic lesions of both cholesterol-fed and WHHL rabbits and showed that MMP-9 along with MMP-1 and MMP-12 was predominately up-regulated compared with aortas of normal wild-type rabbits.[31] As MMP-9 is able to degrade several other ECMs in the arterial wall, we hypothesized that elevation of MMP-9 expression may participate in or mediate atherosclerotic lesion formation To test this hypothesis, we generated transgenic (Tg) rabbits overexpressing rabbit MMP-9 gene in the macrophage lineage and foam cells of atherosclerotic lesions. To the best of our knowledge, this is the first report to demonstrate that overexpression of MMP-9 in macrophages is involved in the progression of atherosclerosis and increases vascular calcification
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