Early increased MT1-MMP expression and late MMP-2 and MMP-9 activity during Angiotensin II induced aneurysm formation.
BACKGROUND
Angiotensin II (Ang II) is associated with a variety of cardiovascular diseases including aneurysm formation. The aim of this study was to evaluate the temporal changes in MT1-matrix metalloproteinase (MMP) and MMP-2 and -9 expression and activity during the course of Ang II induced experimental aneurysm formation.


METHODS
Apolipoprotein E knockout mice (ApoE null) were infused with either 1000 ng/kg/min of Ang II (n = 20) or saline (n = 20) and then sacrificed at 7, 14, 21, and 28 days of infusion (n = 5/group/strain). Aortic diameters were measured by digital microscopy. Systolic blood pressure (SBP) was measured in the rodent tail. Suprarenal abdominal aortas had MT1-MMP mRNA levels and MMP-2 and MMP-9 mRNA levels and activity quantitated using reverse transcriptase-polymerase chain reaction (rt-PCR) and gelatin zymography, respectively. Statistical analyses included nonpaired t-test, Fisher's exact test, and analysis of variance (ANOVA).


RESULTS
Aneurysms occurred in 40, 40, 20, and 80% of ApoE null-Ang II mice at 7, 14, 21, and 28 days, respectively. An early and significant rise in MT1-MMP mRNA occurred in ApoE null mice infused with Ang II mice, while there was no significant change in MMP-2 or MMP-9 mRNA levels. Total MMP-2 and MMP-9 activity increased over time in ApoE null mice infused with Ang II, peaking at 28 days (ANOVA, P < 0.01). SBP was significantly elevated by 7 days in ApoE null mice infused with Ang II compared to ApoE null mice infused with saline (123 +/- 16 versus 102 +/- 6 mm Hg, P < 0.05).


CONCLUSIONS
Angiotensin II induces an early increase in aortic MT1-MMP expression with a subsequent increase in MMP-2 and MMP-9 activity. The process by which these changes cause aneurysm formation warrants further investigation.
Eagleton
Matthew J
MJ
Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA. eagletm@ccf.org
Ballard
Nicole
N
Lynch
Erin
E
Srivastava
Sunita D
SD
Upchurch
Gilbert R
GR
Stanley
James C
JC
D000704:Analysis of Variance; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001014:Aortic Aneurysm / Q000139:chemically induced* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001057:Apolipoproteins E; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14