DUAL EFFECT OF SEROTONIN ON GROWTH OF BOVINE PULMONARY-ARTERY SMOOTH-MUSCLE CELLS IN CULTURE
DUAL EFFECT OF SEROTONIN ON GROWTH OF BOVINE PULMONARY-ARTERY SMOOTH-MUSCLE CELLS IN CULTURE
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DOI：
10.1161/01.res.68.5.1362
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发表时间：
1991-05-01
影响因子：
20.1
通讯作者：
FANBURG, BL
中科院分区：
文献类型：
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作者：
LEE, SL;WANG, WW;FANBURG, BL
我们之前曾报道过，血清素（5-羟色胺[5HT]）通过两种不同的调节机制改变培养的牛肺动脉平滑肌细胞（SMC）的结构。我们现在报道，5HT 还通过这两种相同的机制调节 SMC 生长 - 细胞内启动的刺激事件和细胞表面作用导致的生长抑制。 5HT (1-mu-M) 加 0.1 mM 异丙烟肼（一种 5HT 代谢抑制剂）在 17 - 24 小时孵育后对 SMC 的 DNA 合成（通过 [H-3] 胸苷掺入测量）产生数倍刺激，且细胞 cAMP 仅有轻微升高。这种刺激作用与其他生长因子（包括血小板源性生长因子、成纤维细胞生长因子和表皮生长因子）协同反应，并可通过 5HT 摄取抑制有效逆转。它不是由 5HT 的代谢产物 5-羟基吲哚乙酸产生的。在 1-mu-M 5HT 加 0.1 mM 异丁基甲基黄嘌呤 (IBMX) 存在下，cAMP 升高八倍，发生树突形成，并且 SMC 的 [H-3] 胸苷标记受到抑制。 [H-3]胸苷对标记的抑制作用可通过其他提高细胞 cAMP 的药物（10-mu-M 组胺、1-mu-M 异丙肾上腺素加 0.1 mM IBMX 和 10-mu-M 毛喉素）和 1 mM 二丁酰 cAMP 来模拟。这种抑制作用不会被 5HT 摄取抑制或 5HT 受体拮抗剂酮色林 (5HT2) 阻断；甲硫替平、螺哌隆和米安舍林 (5HT1/5HT2)；和3-托潘基-吲哚-3-羧酸酯和3-托潘基-3,5-二氯苯甲酸酯(5HT3)。然而，与 5HT 类似，5HT1A 激动剂 (+/-)-8-羟基-(+/-)-2-二丙氨基-8-羟基-1,2,3,4-四氢萘氢溴酸盐与 IBMX 结合，可提高 cAMP 并抑制 [H-3] 胸苷标记。 在异丙烟肼或 IBMX 存在的情况下，5HT 不会改变 [Ca2+]i，这表明[Ca2+]i 不是这两种行为的信号。研究表明，5HT 在两个作用点影响 SMC 的生长，一个是通过目前未知的机制在细胞内进行的，另一个是在细胞表面进行的，可能通过一种新的受体并依赖于通过 cAMP 升高进行的信号转导。
We have previously reported that serotonin (5-hydroxytryptamine [5HT]) alters cultured bovine pulmonary artery smooth muscle cell (SMC) configuration through two different regulatory mechanisms. We now report that 5HT also regulates SMC growth through these same two mechanisms - a stimulatory event initiated intracellularly and inhibition of growth resulting from a cell surface action. 5HT (1-mu-M) plus 0.1 mM iproniazid (a 5HT metabolic inhibitor) produced a severalfold stimulation of DNA synthesis (as measured by [H-3]thymidine incorporation) of SMCs after a 17 - 24-hour incubation with only a slight elevation of cellular cAMP. This stimulatory effect responded synergistically with other growth factors including platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor and was effectively reversed by 5HT uptake inhibition. It was not produced by 5-hydroxyindoleacetic acid, a metabolite of 5HT. In the presence of 1-mu-M 5HT plus 0.1 mM isobutylmethylxanthine (IBMX), cAMP was elevated eightfold, dendritic formation occurred, and [H-3]thymidine labeling of SMCs was inhibited. Inhibition of labeling by [H-3]thymidine was mimicked by other agents that elevated cellular cAMP (10-mu-M histamine, 1-mu-M isoproterenol plus 0.1 mM IBMX, and 10-mu-M forskolin) and by 1 mM dibutyryl cAMP. This inhibitory effect was not blocked by either inhibition of 5HT uptake or 5HT-receptor antagonists ketanserin (5HT2); methiothepin, spiperone, and mianserin (5HT1/5HT2); and 3-tropanyl-indole-3-carboxylate and 3-tropanyl-3,5-dichlorobenzoate (5HT3). However, similar to 5HT, the 5HT1A agonist, (+/-)-8-hydroxy-(+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide, in association with IBMX, produced an elevation in cAMP and inhibition of labeling by [H-3]thymidine.5HT, in the presence of either iproniazid or IBMX, did not alter [Ca2+]i, indicating that [Ca2+]i was not a signal for either of these actions. The studies show that 5HT affects SMC growth at two foci of action, one intracellularly by a currently unknown mechanism and another at the cell surface, perhaps via a novel receptor and dependent on transduction of the signal through elevation of cAMP.