Effect of MMP-2 Deficiency on Atherosclerotic Lesion Formation in ApoE-Deficient Mice

Abstract

Objective— Although it has been reported that matrix metalloproteinase (MMP)-2 is a major proteinase in atherosclerotic plaque lesions, there is no direct evidence of the role of MMP-2 in atherosclerotic lesion formation. In the present study we determined the role of MMP-2 in atherosclerosis plaque development using apolipoprotein E-deficient (apoE −/− ) mice. Methods and Results— To generate MMP-2–deficient, apoE-deficient mice (MMP-2 −/− :apoE −/− ), MMP-2 −/− mice were crossed with apoE −/− mice. After 8 weeks of feeding with a lipid-rich diet, morphological and biochemical studies of the aortic sinus and arch were conducted. A significant reduction of the atherosclerotic plaque in the aortic sinus and arch with the decrease in smooth muscle cell-positive area was observed in MMP-2 −/− :apoE −/− mice compared with that of MMP-2 +/+ :apoE −/− mice. Macrophage- and collagen-positive areas were less in aortic sinus but not in aortic arch in MMP-2 −/− :apoE −/− mice. There was no difference of MMP-9 mRNA expression in the plaque lesion between the 2 genotypes. A much lower level of mRNA expression of TIMP-1 and TIMP-2 was detected in the atherosclerotic plaque lesions of MMP-2 −/− :apoE −/− mice than in those of MMP-2 +/+ :apoE −/− mice. Conclusions— MMP-2 contributes to the development of atherosclerosis in apoE −/− mice.