血管紧张素转换酶抑制可调节心脏成纤维细胞生长。
Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth.
作者信息
Grohé C, Kahlert S, Löbbert K, Neyses L, van Eickels M, Stimpel M, Vetter H
机构信息
Medizinische Universitäts-Poliklinik, University of Bonn, Germany.
出版信息
J Hypertens. 1998 Mar;16(3):377-84. doi: 10.1097/00004872-199816030-00015.
BACKGROUND
The progression of left ventricular hypertrophy and cardiac fibrosis in hypertensive heart disease is influenced by sex and age. Although angiotensin converting enzyme inhibition has been shown to prevent progression of the disease in postmenopausal women, the interaction of angiotensin II and estrogen in this process before and after the menopause is poorly understood.
OBJECTIVE
To investigate the influence of the angiotensin converting enzyme inhibitor moexiprilat on serum, estrogen and angiotensin II-induced cardiac fibroblast growth.
METHODS
Neonatal rat cardiac fibroblasts were incubated with 1 and 10% fetal calf serum, 10(-7) mol/l angiotensin II, 10(-9) mol/l estrone, 10(-9) mol/l 17beta-estradiol and 10(-8) mol/l moexiprilat. Proliferation was measured in terms of incorporation of bromodeoxyuridine. Western blot analysis was performed using antibodies directed against the growth-related immediate early genes c-fos and Sp-1. All experiments were performed at least three times.
RESULTS
Fetal calf serum stimulated cardiac fibroblast proliferation (1% fetal calf serum 2.0+/-0.028-fold; 10% fetal calf serum 2.7+/-0.028-fold). Angiotensin II and estrone stimulated proliferation of cardiac fibroblasts grown in the absence of fetal calf serum (angiotensin II 4.2+/-0.075-fold; estrone 2.9+/-0.034-fold) and further increased proliferation in the presence of 1% fetal calf serum (angiotensin 11 4.3+/-0.072-fold); estrone 3.8+/-0.045-fold) and 10% fetal calf serum (angiotensin II 4.8+/-0.112-fold; estrone 4.1+/-0.047-fold). Coincubation with moexiprilat specifically inhibited proliferation induced by angiotensin II and estrone but not by serum, and angiotensin II type 1 receptor blockade inhibited angiotensin II-induced but not estrone-induced cell growth. Western blot analysis showed that the expression of c-fos and Sp-1 was induced in a time-dependent fashion by angiotensin II (to maxima of 5.0-fold for c-fos and 3.0-fold for Sp-1) and estrone (15.2-fold for c-fos and 6.2-fold for Sp-1). This effect was completely inhibited by moexiprilat.
CONCLUSIONS
Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth induced by angiotensin II and estrone. This mechanism might contribute to the beneficial effects of angiotensin converting enzyme inhibition in postmenopausal patients with hypertensive heart disease.
背景
高血压性心脏病中左心室肥厚和心脏纤维化的进展受性别和年龄影响。尽管已证明血管紧张素转换酶抑制可预防绝经后女性疾病进展，但绝经前后血管紧张素 II 与雌激素在此过程中的相互作用仍知之甚少。
目的
研究血管紧张素转换酶抑制剂莫昔普利拉对血清、雌激素和血管紧张素 II 诱导的心脏成纤维细胞生长的影响。
方法
将新生大鼠心脏成纤维细胞与 1%和 10%胎牛血清、10⁻⁷mol/L 血管紧张素 II、10⁻⁹mol/L 雌酮、10⁻⁹mol/L 17β-雌二醇和 10⁻⁸mol/L 莫昔普利拉共同孵育。通过溴脱氧尿苷掺入法测量细胞增殖。使用针对生长相关即刻早期基因 c-fos 和 Sp-1 的抗体进行蛋白质印迹分析。所有实验至少进行三次。
结果
胎牛血清刺激心脏成纤维细胞增殖（1%胎牛血清时为 2.0±0.028 倍；10%胎牛血清时为 2.7±0.028 倍）。血管紧张素 II 和雌酮刺激无胎牛血清培养的心脏成纤维细胞增殖（血管紧张素 II 为 4.2±0.075 倍；雌酮为 2.9±0.034 倍），并在 1%胎牛血清存在时进一步增加增殖（血管紧张素 II 为 4.3±0.072 倍；雌酮为 3.8±0.045 倍）以及 10%胎牛血清存在时（血管紧张素 II 为 4.8±0.112 倍；雌酮为 4.1±0.047 倍）。与莫昔普利拉共同孵育可特异性抑制血管紧张素 II 和雌酮诱导的增殖，但不抑制血清诱导的增殖，并且 1 型血管紧张素 II 受体阻断可抑制血管紧张素 II 诱导的细胞生长，但不抑制雌酮诱导的细胞生长。蛋白质印迹分析表明，血管紧张素 II（c-fos 最高达 5.0 倍，Sp-1 最高达 3.0 倍）和雌酮（c-fos 为 15.2 倍，Sp-1 为 6.2 倍）可时间依赖性诱导 c-fos 和 Sp-1 的表达。莫昔普利拉可完全抑制此效应。
结论
血管紧张素转换酶抑制可调节血管紧张素 II 和雌酮诱导的心脏成纤维细胞生长。该机制可能有助于血管紧张素转换酶抑制对绝经后高血压性心脏病患者的有益作用。
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