Expression of matrix metalloproteinases and TIMPs in human abdominal aortic aneurysms.
Degradation of extracellular matrix, especially elastin, within the aortic wall is a hallmark of abdominal aortic aneurysms (AAAs). Normal turnover of matrix proteins is mediated by a family of enzymes called matrix metalloproteinases (MMPs). MMP activity is regulated by proteins called tissue inhibitors of metalloproteinases (TIMPs). We analyzed the expression of all known MMPs with established elastolytic activity and TIMPs in human AAA and control tissue. mRNA coding for MMP-9, MMP-2, human macrophage metalloelastase, MMP-7, TIMP-1, and TIMP-2 were amplified by reverse transcriptase-PCR in control and AAA tissue. A Northern blot assay was used to measure the levels of mRNA coding for MMP-2, MMP-9, TIMP-1, and TIMP-2. Control aortic tissue was obtained from patients with occlusive disease and from organ donors. The expression of MMP-7 and human macrophage metalloelastase was not detected in any aortic specimens. By Northern blot analysis the mean level of MMP-2 mRNA was not significantly different between control groups and AAAs (normalized values: occlusive, 1.5 +/- 0.8, n = 3; donor, 4.5 +/- 2.2, n = 6; AAA, 4.0 +/- 0.95, n = 15). There was a significant increase in the level of MMP-9 mRNA in AAA specimens (occlusive, 16.8 +/- 3, n = 3; donor, 5.7 +/- 1.2, n = 6; AAA, 56.7 +/- 11, n = 15, p = 0.0069). The levels of mRNA coding for TIMP-1 were not significantly different. There was a small but statistically significant increase in TIMP-2 mRNA in AAA tissue. These data support the hypothesis that increased activity of MMP-9, but not MMP-2, is an important factor in the etiology of AAAs. This enhanced MMP-9 activity could then result in degradation of the ECM, leading to aneurysmal dilatation.
Elmore
J R
JR
Section of Vascular Surgery and Sigfried and Janet Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Keister
B F
BF
Franklin
D P
DP
Youkey
J R
JR
Carey
D J
DJ
D001012:Aorta, Abdominal / Q000201:enzymology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics*; D015152:Blotting, Northern; D017364:Collagenases / Q000235:genetics*; D005109:Extracellular Matrix / Q000201:enzymology; D018093:Gelatinases / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*
D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9