STIMULATION OF SMOOTH MUSCLE CELL GROWTH BY SEROTONIN

描述(摘自摘要)：5-羟色胺(5-HT)可能参与 平滑肌细胞(SMC)所在的肺动脉高压的发病机制 出现增生和肥大。首席调查员发现 5-羟色胺对牛肺组织的增殖和肥大的刺激作用 培养中的动脉系膜细胞。初步观察表明， 细胞内的生长信号是通过5-羟色胺的作用产生的 在这些细胞中的转运蛋白，并与蛋白质酪氨酸密切相关 磷酸化和超氧化物的产生。增强的磷酸化 GTP酶激活蛋白(GAP)是伴随而来的事件之一。 刺激过程。此外，5-羟色胺诱导的这些细胞的生长是 被抗氧化剂和酪氨酸激酶或p21RAS的抑制所阻断。基座 根据这些和其他结果，研究人员假设5-羟色胺转运 通过超氧化物启动细胞增殖和肥大反应 形成和涉及GAP、p21RAS、 RAF-1和MAP激酶。TH STAT转录途径也可能参与其中。 具体目标1将进一步探讨5-羟色胺对蛋白质的影响 SMC的磷酸化信号级联检测MAP激酶级联 上面概述了使用与以前用于GAP的技术类似的技术。 5-羟色胺激活转录因子AP-1、NFkB和STAT 也要进行评估，并将确定这种情况是否发生得彻底 形成超氧化物。特定目标2将进一步评估超氧化物作为一种 SMC生长中的中间信号，并将探讨p21的关系 RAS和MAPK在超氧化物形成中的激活。具体目标3将 评估5-羟色胺对少数已知的其他细胞的影响 含有5-羟色胺转运体或5-羟色胺受体以确定 统一细胞生长的信号通路和下游效应通路 可识别5-羟色胺的诱导作用。具体目标4将决定是否 环核苷酸cAMP和cGMP通过抑制SMC生长 抑制蛋白质磷酸化级联或形成 超氧化物。特定的人工智能5将利用聚合酶链式反应方法来确定 低氧刺激5-羟色胺摄取是通过增强 5-羟色胺转运体AN的转录将决定SMC是否预先暴露 低氧可增强5-羟色胺诱导的信号通路 导致SMC的增生和肥大。

DESCRIPTION (from abstract): Serotonin (5-HT) may participate in the pathogenesis of pulmonary hypertension where smooth muscle cell (SMC) hyperplasia and hypertrophy occur. The principle investigator has found that 5-HT stimulates both hyperplasia and hypertrophy of bovine pulmonary artery SMCs in culture. Preliminary observations indicate that intracellular signalin for growth occurs through action of a 5-HT transporter in these cells and is closely linked to protein tyrosine phosphorylation and production of superoxide. Enhanced phosphorylation of GTPase-activating protein (GAP) is one of the events that accompanies the stimulatory process. Furthermore, 5-HT-induced growth of these cells is blocked by anti-oxidants and inhibition of tyrosine kinase or p21 Ras. Based on these and other results the investigators postulate that 5-HT transport initiates a cellular proliferative and hypertrophic response via superoxide formation and a protein phosphorylation cascade that involves GAP, p21 Ras, Raf-1, and MAP kinases. Th STAT transcription pathway may also be involved. Specific aim 1 will further explore the effect of 5-HT on the protein phosphorylation signaling cascade of SMCs examining the MAP kinase cascade outlined above using techniques similar to those previously used for GAP. Activation of the transcription factors AP-1 NFkB, and STAT by 5-HT will also be assessed and it will be determined if this occurs thorough superoxide formation. Specific aim 2 will further evaluate superoxide as an intermediate signal in SMC growth and will explore the relationship of p21 Ras and MAPK activations in superoxide formation. Specific aim 3 will evaluate the influence of 5-HT on a limited number of other cells known to contain either 5-HT transporter or the 5-HT receptor to determine if unifying signaling and downstream effector pathways for cellular growth induce by 5-HT can be identified. Specific aim 4 will determine if the cyclic nucleotides, cAMP and cGMP, cause inhibition of SMC growth through inhibition of the protein phosphorylation cascade or formation of superoxide. Specific ai 5 will utilize PCR methodology to determine if stimulation of 5-HT uptake by hypoxia occurs through enhancement of transcription of the 5-HT transporter an will determine if SMCs pre-exposed to hypoxia demonstrate enhancement of 5-HT-induced signaling pathways that lead to SMC hyperplasia and hypertrophy.