Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms.
BACKGROUND
Selective estrogen receptor modulators (SERMs), similar to estrogens, possess vasoprotective effects by reducing release of reactive oxygen species. Little is known about the potential effects of SERMs on the pathogenesis of abdominal aortic aneurysms (AAAs). This study's objective was to investigate the growth of experimental AAAs in the setting of the SERM tamoxifen.


METHODS
In the first set of experiments, adult male rats underwent subcutaneous tamoxifen pellet (delivering 10 mg/kg/day) implantation (n = 14) or sham operation (n = 16). Seven days later, all animals underwent pancreatic elastase perfusion of the abdominal aorta. Aortic diameters were determined at that time, and aortas were harvested 7 and 14 days after elastase perfusion for immunohistochemistry, real-time polymerase chain reaction, Western blot analysis, and zymography. In the second set of experiments, a direct irreversible catalase inhibitor, 3-amino-1,2,4-triazole (AT), was administered intraperitoneally (1 mg/kg) daily to tamoxifen-treated (n = 6) and control rats (n = 6), starting on day 7 after elastase perfusion. Aortic diameters were measured on day 14. In a third set of experiments, rats were perfused with catalase (150 mg/kg) after the elastase (n = 5), followed by daily intravenous injections of catalase (150 mg/kg/day) administered for 10 days. A control group of rats (n = 7) received 0.9% NaCl instead of catalase.


RESULTS
Mean AAA diameters were approximately 50% smaller in tamoxifen-treated rats compared with sham rats 14 days after elastase perfusion (P = .002). The tamoxifen-treated group's aortas had a five-fold increase in catalase mRNA expression (P = .02) on day 7 and an eight-fold increase in catalase protein on day 14 (P = .04). Matrix metalloprotroteinase-9 activity was 2.4-fold higher (P = .01) on day 7 in the aortas of the controls compared to the tamoxifen-treated group's aortas. Tamoxifen-treated rats had approximately 40% fewer aortic polymorphonuclear neutrophils compared to controls on day 7 (P = .05). Administration of the direct catalase inhibitor AT to tamoxifen-treated rats partially reversed the aneurysm inhibitory effect of tamoxifen by nearly 30% (P = .02). In contrast, catalase administration inhibited AAA formation by 44% (P = .002).


CONCLUSIONS
The selective estrogen receptor modulator tamoxifen inhibits the development of AAAs in male rats in association with an up-regulation of catalase and inhibition of aortic wall neutrophil infiltration.
Grigoryants
Vladimir
V
Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Hannawa
Kevin K
KK
Pearce
Charles G
CG
Sinha
Indranil
I
Roelofs
Karen J
KJ
Ailawadi
Gorav
G
Deatrick
Kristopher B
KB
Woodrum
Derek T
DT
Cho
Brenda S
BS
Henke
Peter K
PK
Stanley
James C
JC
Eagleton
Matthew J
MJ
Upchurch
Gilbert R
GR
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000517:prevention & control*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020556:Neutrophil Infiltration / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation
D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D002374:Catalase; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; D000640:Amitrole