Tamoxifen treatment of myocardial infarcted female rats exacerbates scar formation

Abstract

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.

The plating of rat scar myofibroblasts on matrigel unmasks a novel phenotype; the self assembly of lumen‐like structures

“…The cardiac fibroblast populations can also be distinguished by nestin expression, as the intermediate filament protein was highly expressed in neonatal rat ventricular fibroblasts, significantly downregulated in adult ventricular fibroblasts and re‐induced in a subpopulation of scar myofibroblasts [Beguin et al, 2012]. The present study has further demonstrated that scar myofibroblasts plated alone on matrigel in the absence of an angiogenic peptide were capable of self assembly and formation of lumen‐like structures akin to that reported by endothelial cells [Geraldes et al, 2007]. By contrast, neither neonatal nor adult ventricular fibroblasts were capable of recapitulating an endothelial cell‐like response when plated on matrigel.…”

“…Myocardial infarction (MI) was induced in male Sprague–Dawley rats (9–11 weeks old; Charles Rivers, St. Constant, Canada) following ligation of the left anterior descending coronary artery as previously described [Geraldes et al, 2007]. Scar myofibroblasts were isolated from the infarct region of 1‐week post‐MI male rats and adult cardiac fibroblasts isolated from the left ventricle of normal male Sprague–Dawley rats (9–11 weeks old; Charles Rivers), as previously described [Calderone et al, 2006; Beguin et al, 2012].…”

“…Ice‐cold matrigel (100 µl; BD Biosciences) poured in 24‐well plates was allowed to solidify for 30 min at 37°C, as previously described [Geraldes et al, 2007]. First, 2nd, or 3rd passage myofibrolasts, 1st passage neonatal and adult ventricular fibroblasts (25,000 cells/well of a 24‐well plate) were plated on matrigel in the absence or presence of TGF‐β 1 (1 ng/ml), TGF‐β 3 (1 ng/ml), or TGF‐β R1 kinase inhibitor II (100 nM; a cell‐permeable and selective ATP‐competitive inhibitor of TGF‐β type I receptor; Calbiochem, La Jolla, CA).…”

Rapamycin treatment unmasks a sex‐specific pattern of scar expansion of the infarcted rat heart: The relationship between mTOR and KATP channel

“…[4][5][6][7][8] The smaller infarct was not attributed to the presence of estrogen and progesterone as ovariectomized adult female rodents subjected to complete coronary artery ligation did not translate to scar expansion. [9][10][11][12] Moreover, experimental studies performed in rodents reported that recruitment of cardiac sarcolemma K ATP channels provided sex-specific cardioprotection to the female adult rodent heart in response to ischemic injury. 4,5 The cardiac K ATP channel is composed of the pore-forming subunit Kir6.2 and the auxiliary sulfonylurea receptor subunit SUR2A and channel activity rapidly adjusted membrane excitability in response to changes in the energetic status of the cell.…”

“…The latter paradigm extended to rodents as a smaller infarct size was identified in females compared to males in experimental models of ischemic injury 4–8 . The smaller infarct was not attributed to the presence of estrogen and progesterone as ovariectomized adult female rodents subjected to complete coronary artery ligation did not translate to scar expansion 9–12 . Moreover, experimental studies performed in rodents reported that recruitment of cardiac sarcolemma K ATP channels provided sex‐specific cardioprotection to the female adult rodent heart in response to ischemic injury 4,5 .…”