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 these MMPs in aneurysm formation.

• Authors: Aernout Luttun, Esther Lutgens, Ann Manderveld, Katleen Maris, Désiré Collen, Peter Carmeliet, Lieve Moons
• Journal: Circulation (Circulation) Vol. 109 Issue 11 Pg. 1408-14 (Mar 23 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 14993123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Collagen
• Elastin
• Metalloendopeptidases
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase 12

Topics

• Animals
• Aortic Diseases (enzymology, etiology, pathology)
• Apolipoproteins E (deficiency, genetics)
• Arteriosclerosis (enzymology, etiology, pathology)
• Collagen (metabolism)
• Diet, Atherogenic
• Dilatation, Pathologic
• Elastin (metabolism)
• Extracellular Matrix (pathology)
• Female
• Hypercholesterolemia (complications)
• Macrophages (pathology)
• Matrix Metalloproteinase 12
• Matrix Metalloproteinase 9 (deficiency, genetics, physiology)
• Metalloendopeptidases (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Tunica Media (pathology)