Expression of matrix metalloproteinases and their inhibitors in aneurysms and normal aorta.
BACKGROUND
Abdominal aortic aneurysms (AAAs) are characterized by degradation of collagen and elastin resulting from increases in matrix metalloproteinase (MMP) activity. Previous authors have identified isolated increases in expression of specific MMPs in AAAs, but none have compared relative levels of expression of particular MMPs to one another or to those of their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). This study proposes to quantify relative mRNA levels for interstitial collagenase (MMP-1), 72 kd type IV collagenase (MMP-2), 92 kd type IV collagenase (MMP-9), TIMP-1, and TIMP-2 in normal aorta (NA) and AAA to provide insight as to the relative importance of each in aneurysm formation.


METHODS
Competitive polymerase chain reactions (PCRs) with gene-specific external standards and cDNA derived from AAAs (n = 8; mean age, 67.4 years) and NA (n = 5; mean age, 40.6 years) were used to quantify mRNA levels. Results were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels, determined by means of competitive PCR, and compared by means of Mann-Whitney statistics.


RESULTS
Significant increases in MMP mRNA expression in AAA over NA were observed for MMP-1 (3.64 versus 0.3, p = 0.007), MMP-9 (78.03 versus 3.35, p = 0.003), TIMP-1 (835.32 versus 477.2, p = 0.027), and TIMP-2 (18.09 versus 4.14, p = 0.003). The ratio of MMP to TIMP mRNA levels was higher in AAA than NA (0.135 versus 0.045, p = 0.018).


CONCLUSIONS
Increases in expression of MMP-1, MMP-9, and MMP/TIMP ratios may result in increased proteolysis and matrix degradation, which characterize AAAs. MMP-9 appears to be the predominant metalloproteinase expressed in AAA, because its mRNA levels were more than 20 times and 2 times higher than those of MMP-1 and MMP-2, respectively. TIMP-1 mRNA levels were in molar excess to those of any of the metalloproteinases studied.
Tamarina
N A
NA
Department of Surgery, Northwestern University Medical School, Chicago, Ill., USA.
McMillan
W D
WD
Shively
V P
VP
Pearce
W H
WH
D000328:Adult; D000368:Aged; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000601:surgery; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000601:surgery; D001483:Base Sequence; D017364:Collagenases / Q000096:biosynthesis; D017931:DNA Primers; D005260:Female; D018093:Gelatinases / Q000096:biosynthesis; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011480:Protease Inhibitors / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012016:Reference Values; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases
D017931:DNA Primers; D006023:Glycoproteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1