Loss of Matrix Metalloproteinase-9 or Matrix Metalloproteinase-12 Protects Apolipoprotein E–Deficient Mice Against Atherosclerotic Media Destruction but Differentially Affects Plaque Growth

Abstract

Background-Epidemiological and histological evidence implicates proteinases of the matrix metalloproteinase (MMP) family in atherosclerosis and aneurysm formation. We previously indicated a role for urokinase-type plasminogen activator in atherosclerotic media destruction by proteolytic activation of MMPs. However, the role of specific MMPs, such as MMP-9 and MMP-12, in atherosclerosis remains undefined. Methods and Results-MMP-9 -or MMP-12-deficient mice were crossed in the atherosclerosis-prone apolipoprotein E-deficient background and fed a cholesterol-rich diet. Mice were killed at 15 or 25 weeks of diet to study intermediate and advanced lesions, respectively. Loss of MMP-9 reduced atherosclerotic burden throughout the aorta and impaired macrophage infiltration and collagen deposition, while MMP-12 deficiency did not affect lesion growth. MMP-9 or MMP-12 deficiency conferred significant protection against transmedial elastin degradation and ectasia in the atherosclerotic media. Conclusions-This study is the first to provide direct genetic evidence for a significant involvement of MMP-9, but not of MMP-12, in atherosclerotic plaque growth. In addition, deficiency of MMP-9 or MMP-12 protected apolipoprotein E-deficient mice against atherosclerotic media destruction and ectasia, mechanisms that implicate the involvement of

Collagens in the progression and complications of atherosclerosis

“…Targeted deletion of either MMP-12 or MMP-13 in the ApoE-null mouse had no effect on plaque size, nor on the cellular composition of the plaques. 100,104 However, there were increases in fibrillar collagen content, and fibril size and alignment in the fibrous caps of the MMP-13-null mice. 104 The latter observation is not surprising, considering that MMP-13 functions as a principle collagenase in the mouse.…”

“…Deletion of MMP-9 resulted in decreased plaque volume, although there were discrepancies between studies as to whether SMC or macrophage infiltration into the plaques was affected by proteinase deficiency. [98][99][100] Deletion of MMP-2 in the ApoE-null mouse resulted in decreased plaque size, concomitant with the decreased accumulation of SMCs and macrophages in the plaque. 101 Thus, MMP-2 and MMP-9 have been identified as proatherogenic MMPs mediating the migration of both SMCs and inflammatory cells in the atherosclerotic plaque.…”

Gelatinase-mediated migration and invasion of cancer cells

“…The gelatinases are also implicated in cardiovascular diseases. Loss of MMP-9 gene in atherosclerosis-prone mice reduced the growth of atherosclerotic lesions, and protected mice from the destruction of the atherosclerotic media implicating that MMP-9 is intimately involved in the pathogenesis of atherosclerosis (Luttun et al, 2004). The phenotype of MMP-2 deficient mice is relatively mild with minor defects in developmental angiogenesis and in the skeleton and joints (Corry et al, 2002;Itoh et al, 1998).…”

Matrix metalloproteinases in cardiovascular disease

“…The presence of inflammatory cells, such as activated macrophages and T cells in the advancing zone of the atherosclerotic plaque, helps to accelerate this process (10). Recently, studies using transgenic knockout mice deficient in MMP-9, when crossed with the atherogenic apolipoprotein E knockout mice, despite cholesterol feeding showed much less atherosclerotic burden (11). This was not replicated by MMP-12 knockout animals.…”