Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits: relationship to lesion development

Am J Pathol. 1998 Jul;153(1):109-19. doi: 10.1016/s0002-9440(10)65551-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / enzymology*
  • Arteriosclerosis / enzymology*
  • Blotting, Northern
  • Blotting, Western
  • COS Cells
  • Cells, Cultured
  • Cholesterol, Dietary / administration & dosage
  • Cholesterol, Dietary / blood
  • Collagen / metabolism
  • Diet, Atherogenic
  • Enzyme Precursors / metabolism
  • Fibronectins / metabolism
  • Gelatinases / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Immunoenzyme Techniques
  • Lipoproteins, LDL / pharmacology
  • Macrophages / enzymology
  • Male
  • Matrix Metalloproteinase 12
  • Metalloendopeptidases / metabolism*
  • Rabbits

Substances

  • Cholesterol, Dietary
  • Enzyme Precursors
  • Fibronectins
  • Lipoproteins, LDL
  • acetyl-LDL
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Collagen
  • Gelatinases
  • Metalloendopeptidases
  • progelatinase
  • prostromelysin
  • MMP12 protein, human
  • Matrix Metalloproteinase 12