A role of matrix metalloproteinase-8 in atherosclerosis.
BACKGROUND
Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I.


OBJECTIVE
We studied whether MMP8 plays a role in atherogenesis.


RESULTS
In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8-deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing that Ang I cleavage by MMP8 generated Ang II, MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule (VCAM)-1 expression and that MMP8-deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship among MMP8 gene variation, plasma VCAM-1 level, and atherosclerosis progression was also observed in a population-based, prospective study.


CONCLUSIONS
These results indicate that MMP8 is an important player in atherosclerosis.
Laxton
Ross C
RC
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Hu
Yanhua
Y
Duchene
Johan
J
Zhang
Feng
F
Zhang
Zhongyi
Z
Leung
Kit-Yi
KY
Xiao
Qingzhong
Q
Scotland
Ramona S
RS
Hodgkinson
Conrad P
CP
Smith
Katherine
K
Willeit
Johann
J
López-Otín
Carlos
C
Simpson
Iain A
IA
Kiechl
Stefan
S
Ahluwalia
Amrita
A
Xu
Qingbo
Q
Ye
Shu
S
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001794:Blood Pressure; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D023921:Coronary Stenosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D036904:Leukocyte Rolling; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012720:Severity of Illness Index; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D003094:Collagen; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8