ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis.
Matrix metalloproteinase-1 (MMP-1), or interstitial collagenase, has been hypothesized to contribute to the progression of the human atherosclerotic lesions by digesting the fibrillar collagens of the neointimal ECM. The apolipoprotein E knockout (apoE0) mouse model develops complex atherosclerotic lesions, but mice do not possess a homologue for MMP-1. To provide an in vivo evaluation of the role of MMP-1 in atherogenesis, we created a transgenic mouse model that expresses this enzyme specifically in the macrophage, under the control of the scavenger receptor A (SCAV) enhancer/promoter. The MMP-1 transgenic mice were crossed into the apoE0 background and fed an atherogenic diet for 16-25 weeks. Surprisingly, the transgenic mice demonstrated decreased lesion size compared with control littermates. The lesions of the transgenic animals were less extensive and immature, with fewer cellular layers and a diminished content of fibrillar collagen. There was no evidence of plaque rupture. Our data suggest that remodeling of the neointimal extracellular matrix by MMP-1 is beneficial in the progression of lesions.
Lemaître
V
V
Division of Molecular Medicine, Department of Medicine, and. Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
O'Byrne
T K
TK
Borczuk
A C
AC
Okada
Y
Y
Tall
A R
AR
D'Armiento
J
J
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002634:Chemotaxis, Leukocyte; D004036:Diet, Atherogenic; D006801:Humans; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic
D001057:Apolipoproteins E; D020781:Matrix Metalloproteinase 1