Bradykinin-induced reductions in collagen gene expression involve prostacyclin
Bradykinin-induced reductions in collagen gene expression involve prostacyclin
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DOI：
10.1161/01.hyp.32.1.84
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发表时间：
1998-07-01
期刊：
影响因子：
8.3
通讯作者：
Printz, MP
中科院分区：
文献类型：
--
作者：
Gallagher, AM;Yu, H;Printz, MP
心肌梗死和慢性高血压后的心肌纤维化与心肌内胶原合成和沉积的增加有关。血管紧张素转换酶（ACE）抑制剂限制肥大和纤维化；它们的作用机制仍有争议，尽管激肽已被认为发挥了作用。由于缓激肽和前列腺素（PG）均可降低心脏成纤维细胞中的胶原基因表达，因此本研究的目的是确定缓激肽的作用是否通过心脏成纤维细胞增强前列腺素的形成来介导。缓激肽使[H-3]花生四烯酸代谢物的释放比对照组增加2.3倍，并刺激这些细胞释放的6-酮PGF(1 α) （PGI的稳定代谢物(2)）呈剂量依赖性增加，其中1 nmol/L缓激肽使6-酮PGF（1 α）释放增加4倍。Beraprost（一种PGI(2)类似物）使稳态前α 1(I)和前α 1（III）胶原mRNA水平分别降低35.6+/-6.6%和34.2+/-10.0%。吲哚美辛预处理可逆转缓激肽诱导的I型和III型胶原基因表达的降低。我们的研究结果表明，缓激肽通过兔心脏成纤维细胞调节胶原生物合成的一种机制涉及花生四烯酸代谢物的形成，特别是PGI(2)。本研究的结果表明，内源性激肽的稳定（如ACE抑制剂）会增加前列环素的产生，导致胶原基因表达的衰减，对心肌内胶原的合成和沉积有潜在的影响。
Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [H-3]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF(1 alpha) (the stable metabolite of PGI(2)) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF(1 alpha) release. Beraprost (a PGI(2) analogue) reduced steady-state pro alpha 1(I) and pro alpha 1(III) collagen mRNA levels by 35.6+/-6.6% and 34.2+/-10.0%, respectively. Bradykinin-induced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI(2). The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium.