莫昔普利拉对雌激素刺激的心脏成纤维细胞生长的影响。

Effects of moexiprilat on oestrogen-stimulated cardiac fibroblast growth.

作者信息

Grohé C, Kahlert S, Lóbbert K, van Eickels M, Stimpel M, Vetter H, Neyses L

机构信息

Medizinische Universitäts-Poliklinik, University of Bonn, Germany.

出版信息

Br J Pharmacol. 1997 Aug;121(7):1350-4. doi: 10.1038/sj.bjp.0701263.

DOI:10.1038/sj.bjp.0701263

PMID:9257913

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1564823/

Abstract

The effects of 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)-[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat), 17beta-oestradiol (E2), oestrone (ES) and angiotensin II (AII) on growth and activation of oestrogen receptors and the immediate-early gene egr-1 were investigated in neonatal rat cardiac fibroblasts of female and male origin. 2. In BrdU proliferation assays, oestrone (10(-7)- 10(-9) M) stimulated cardiac fibroblast growth in a concentration-dependent fashion (maximum at 10(-7) M, 4.0 fold +/- 0.14 in female and 3.1 fold +/- 0.06 in male cells, n=9, P<0.05), while E2 (10(-7)-10(-9) M) had no effect. Moexiprilat (10(-7)M) completely inhibited oestrone-induced cardiac fibroblast growth. 3. Angiotensin II (10(-7) M) induced cardiac fibroblast growth (female 4.1 fold +/- 0.1/male 3.9 fold +/- 0.2; n=9, P<0.05). Angiotensin II induced oestrogen receptor (maximum 21.8 fold at 60 min) and egr-1 (maximum 47.5 fold at 60 min) expression in a time-dependent fashion. 4. In immunoblot experiments, oestrogen activated oestrogen receptor (ES: 12.8 fold +/- 2.0; E2: 14.7 fold +/- 4.9; n=3, P<0.05) and egr-1 (ES: 5.1 fold, +/- 0.24; E2: 3.8 fold, +/- 0.25; n=3, P<0.05) expression. The induction of oestrogen receptor and egr-1 protein expression was time-dependent and inhibited by moexiprilat. 5. Our results show that oestrone and 17beta-oestradiol reveal a significant difference in their potential to activate cardiac fibroblast growth in female and male cells and that oestrone-stimulated growth is inhibited by moexiprilat. The inhibition of oestrone-stimulated cardiac fibroblast growth by moexiprilat may contribute to the beneficial effects seen in postmenopausal women with hypertensive heart disease treated with ACE inhibitors.

摘要

研究了2-2-(1-(乙氧羰基)-3-苯基丙基)-[氨基氧丙基]-6,7-二甲氧基-1,2,3,4-四氢异喹啉-3-羧酸（莫昔普利拉）、17β-雌二醇（E2）、雌酮（ES）和血管紧张素II（AII）对源自雌性和雄性新生大鼠心脏成纤维细胞雌激素受体及即刻早期基因egr-1生长和激活的影响。2. 在BrdU增殖试验中，雌酮（10⁻⁷ - 10⁻⁹ M）以浓度依赖性方式刺激心脏成纤维细胞生长（在10⁻⁷ M时达到最大值，雌性细胞中为4.0倍±0.14，雄性细胞中为3.1倍±0.06，n = 9，P < 0.05），而E2（10⁻⁷ - 10⁻⁹ M）无作用。莫昔普利拉（10⁻⁷ M）完全抑制雌酮诱导的心脏成纤维细胞生长。3. 血管紧张素II（10⁻⁷ M）诱导心脏成纤维细胞生长（雌性为4.1倍±0.1/雄性为3.9倍±0.2；n = 9，P < 0.05）。血管紧张素II以时间依赖性方式诱导雌激素受体（60分钟时最大值为21.8倍）和egr-1（60分钟时最大值为47.5倍）表达。4. 在免疫印迹实验中，雌激素激活雌激素受体（ES：12.8倍±2.0；E2：14.7倍±4.9；n = 3，P < 0.05）和egr-1（ES：5.1倍，±0.24；E2：3.8倍，±0.25；n = 3，P < 0.05）表达。雌激素受体和egr-1蛋白表达的诱导具有时间依赖性且被莫昔普利拉抑制。5. 我们的结果表明，雌酮和17β-雌二醇在激活雌性和雄性细胞心脏成纤维细胞生长的潜力上存在显著差异，且莫昔普利拉可抑制雌酮刺激的生长。莫昔普利拉对雌酮刺激的心脏成纤维细胞生长的抑制作用可能有助于解释用ACE抑制剂治疗的绝经后高血压心脏病女性所观察到的有益效果。