Transgenic expression of matrix metalloproteinase-9 modulates collagen deposition in a mouse model of atherosclerosis.
Matrix metalloproteinase-9 (MMP-9) has been proposed to be an important modulator of atherosclerotic plaque vulnerability. We generated a transgenic (tg) model expressing human proMMP-9 in macrophages, using the scavenger receptor enhancer/promoter A. This model was crossed into the double Apoe/Timp-1 knockout background. After 16 weeks of a high-fat diet, there were no significant changes in plaque size in the proximal aortas between the four groups of the study population (Apoe(-/-), Apoe(-/-)/MMP-9tg, Apoe(-/-)/Timp-1(-/-), and Apoe(-/-)/MMP-9tg/Timp-1(-/-)), and, in the Timp-1 knockout background, MMP-9 transgenic mice and control littermates had similar micro-aneurysm formation. However, lesions in Apoe(-/-)/MMP-9tg/Timp-1(-/-) mice contained significantly more collagen compared to the three other groups (P<0.005). Culture supernatants from elicited Apoe(-/-)/MMP-9tg/Timp-1(-/-) macrophages contained higher levels of active TGF-beta than the three other groups (P<0.05), suggesting that augmented collagen deposition resulted from an increase in TGF-beta activation due to transgenic MMP-9 in the Timp-1(-/-) background. This study indicates that, in human atherosclerosis, increased MMP-9 activity could up-regulate collagen deposition, possibly through TGF-beta activation.
Lemaître
Vincent
V
Department of Medicine, Division of Molecular Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Kim
Henry E
HE
Forney-Prescott
Margaret
M
Okada
Yasunori
Y
D'Armiento
Jeanine
J
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics*; D003094:Collagen / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019076:Transgenes
D016212:Transforming Growth Factor beta; D003094:Collagen; D020780:Matrix Metalloproteinase 9