Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits: relationship to lesion development.
Degradation of extracellular matrix (ECM) proteins in the aorta is a critical step for the development of atherosclerosis. Expression of matrix metalloproteinase (MMP)-12 (macrophage elastase), an elastin-degrading proteinase in the MMP family, was investigated in the thoracic aorta of rabbits fed a 1% cholesterol-containing diet for 16 weeks. In the atherosclerotic lesions, MMP-12 was produced abundantly at both the mRNA and protein levels, whereas no expression was observed in the normal rabbit aortas. The principal source of MMP-12 was macrophage foam cells (MFCs) that had infiltrated the atherosclerotic intima; this was demonstrated in both in vitro culture studies of MFCs purified from atherosclerotic lesions and immunohistochemical studies of aortic lesions. Additional biochemical studies using recombinant rabbit MMP-12 revealed that MMP-12 digested elastin, type IV collagen, and fibronectin and also activated MMP-2 and MMP-3. Expression of MMP-12 by human macrophage cell lines was increased by stimulation with acetylated low-density lipoprotein, implying augmentation of MMP-12 production during foam cell formation. Increased expression of MMP-12 in atherosclerotic lesions, concomitant with foam cell generation, which triggers the acceleration of ECM breakdown, is likely to be a critical step in the initiation and progression of the atherosclerotic cascade.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan. matsumot@yamanouchi.co.jp
S
S
Matsumoto
T
T
Kobayashi
M
M
Katoh
S
S
Saito
Y
Y
Ikeda
M
M
Kobori
Y
Y
Masuho
T
T
Watanabe
D000818:Animals; D001011:Aorta / Q000201:enzymology*; D001161:Arteriosclerosis / Q000201:enzymology*; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000097:blood; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004792:Enzyme Precursors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000378:metabolism*; D011817:Rabbits
D002791:Cholesterol, Dietary; D004792:Enzyme Precursors; D005353:Fibronectins; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; C048047:prostromelysin; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12