Tamoxifen treatment of myocardial infarcted female rats exacerbates scar formation.
Hormonal replacement therapy in postmenopausal women was associated with an increased incidence of nonfatal myocardial infarction. Selective estrogen receptor modulators were considered an alternative pharmacological approach. However, selective estrogen receptor modulators acting via estrogen receptor-dependent and receptor-independent mechanisms may negatively influence cardiac remodeling. The present study tested the hypothesis that tamoxifen (TAM) treatment after coronary artery ligation compromised scar formation. TAM administration (10 mg kg(-1) day(-1) for 3 weeks) to postmyocardial infarcted (MI) female adult rats significantly increased scar surface area (TAM+MI = 0.67 +/- 0.08 vs MI = 0.45 +/- 0.06 cm(2)) and weight (TAM+MI = 0.071 +/- 0.007 vs MI = 0.050 +/- 0.006 grams). In the infarct region, a significant decrease (p < 0.05) of small calibre vessels (lumen diameter <50 microm) was observed in TAM treated post-MI rats (4.5 +/- 0.8 vessels/mm(2)), as compared to untreated MI rats (7 +/- 0.7 vessels/mm(2)). Consistent with the latter finding, 4-OH TAM caused a dose-dependent suppression of vascular endothelial growth factor (VEGF)-stimulated (10(-9) mol/l) capillarity-like tubule formation by rat aortic endothelial cells in vitro via an estrogen receptor-independent mechanism. These data have demonstrated that TAM treatment of post-MI female rats exacerbated scar formation and may have occurred at least in part via the attenuation of new vessel formation in the infarct region.
Geraldes
Pedro
P
Research Centre, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, H1T 1C8, Canada.
Gosselin
Hugues
H
Tanguay
Jean-François
JF
Clément
Robert
R
Calderone
Angelino
A
D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D002921:Cicatrix / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D066298:In Vitro Techniques; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D009320:Atrial Natriuretic Factor; D015820:Cadherins; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C467498:vascular endothelial growth factor A, rat