Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery
Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery
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DOI：
10.1165/ajrcmb.26.2.4695
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发表时间：
2002-02-01
影响因子：
6.4
通讯作者：
Tinker, A
中科院分区：
文献类型：
--
作者：
Clapp, LH;Finney, P;Tinker, A
原发性肺动脉高压的特点是肺血管阻力增加和平滑肌增生。稳定的类似物越来越多地用于治疗这种疾病，尽管没有数据比较它们对增殖的影响。因此，我们研究了几种前列环素（PGI(2)）类似物对人肺动脉平滑肌细胞的抗增殖活性，包括UT-15和伊洛前列素，这些类似物最近已经完成了成功的临床试验。通过[h -3]胸腺嘧啶掺入（30 h）或细胞数量（48 h）来评估，血清诱导的增殖被显著抑制，效力差异为10倍，有效性排名UT-15 b> iloprost > cicaprost > beraprost。腺苷酸环化酶抑制剂2,5'-二脱氧腺苷（DDA）可逆转上述作用，而SQ22536则不能。尽管SQ22536是一种高度可变的抑制剂，但细胞内环AMP （cAMP）被所有类似物升高，并被DDA抑制，这表明不同的途径可能介导cAMP的产生。与其他类似物相比，UT-15产生了更大、更持续的cAMP增加，伊洛前列素是最弱的提升。因此，PGI(2)类似物可能通过cAMP依赖性途径有效抑制人肺动脉的增殖，尽管cAMP升高本身并不是抗增殖能力的良好预测指标。
Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. We therefore investigated the anti proliferative activity of several prostacyclin (PGI(2)) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Serum-induced proliferation, as assessed by [H-3]thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'-dideoxyadenosine (DDA) but not SQ22536. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Thus, PGI(2) analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency.