Fujisaki H, Ito H, Hirata Y, Tanaka M, Hata M, Lin M, Adachi S, Akimoto H, Marumo F, Hiroe M
Second Department of Internal Medicine, Tokyo Medical & Dental University, Japan.
J Clin Invest. 1995 Aug;96(2):1059-65. doi: 10.1172/JCI118092.
The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
本研究旨在检测内皮素 -1（ET -1）作为心脏成纤维细胞可能的自分泌/旁分泌生长因子的作用，并研究其与心脏利钠激素的相互作用。用大鼠前内皮素原 -1（ppET -1）cDNA作为探针，通过Northern印迹分析证实了新生大鼠培养的心脏成纤维细胞中ppET -1 mRNA的表达。血管紧张素II（ANG II）和ET -1可短暂（30分钟）增加心脏成纤维细胞中稳态ppET -1 mRNA水平。ET -1和ANG II均显著刺激[3H]胸苷掺入心脏成纤维细胞，ETA受体拮抗剂（BQ123）可剂量依赖性地抑制其作用，BQ-123还抑制ET -1和ANG II诱导的ppET -1 mRNA表达。心房利钠肽和脑利钠肽（ANP、BNP）均可激活颗粒型鸟苷酸环化酶，它们抑制ANG II和ET -1刺激的ppET -1 mRNA表达及[3H]胸苷掺入。硝普钠（一种可溶性鸟苷酸环化酶激活剂）和8 -溴环鸟苷酸（一种可透过细胞膜的cGMP衍生物）同样抑制ppET -1 mRNA表达及[3H]胸苷掺入。BNP抑制ANG II和ET -1刺激的DNA合成的作用比ANP更强，而BNP和ANP在刺激心脏成纤维细胞产生cGMP方面几乎等效。我们的数据表明，ANG II和ET -1部分通过环鸟苷酸依赖性机制上调大鼠心脏成纤维细胞中ET -1基因表达，利钠肽可能通过抑制ET -1基因表达来抑制ANG II刺激的心脏成纤维细胞增殖。我们的数据提示内源性ET -1作为心脏成纤维细胞自分泌/旁分泌生长因子的可能作用及其在心脏纤维化调节中与利钠肽的密切相互作用。
