Banes Amy K L, Shaw Seán M, Tawfik Amany, Patel Bela P, Ogbi Safia, Fulton David, Marrero Mario B
Vascular Biology Center, Medical College of Georgia, CB-3301, Augusta, GA 30912-2500, USA.
Am J Physiol Cell Physiol. 2005 Apr;288(4):C805-12. doi: 10.1152/ajpcell.00385.2004. Epub 2004 Dec 15.
Serotonin (5-hydroxytryptamine, 5-HT) is a vasoconstrictor and mitogen whose levels are elevated in diabetes. Previous studies have shown the presence of 5-HT2A, 5-HT2B, and 5-HT1B receptors in vascular smooth muscle cells (VSMCs). There are currently no data regarding 5-HT2B and 5-HT1B receptor activation of the JAK/STAT pathway in VSMCs and resultant potential alterations in 5-HT signaling in diabetes. Therefore, we tested the hypothesis that 5-HT differentially activates the JAK/STAT pathway in VSMCs under conditions of normal (5 mM) and high (25 mM) glucose. Treatment of rat VSMCs with 5-HT (10(-6) M) resulted in time-dependent activation ( approximately 2-fold) of JAK2, JAK1, and STAT1, but not STAT3 (maximal at 5 min, returned to baseline by 30 min). The 5-HT2B receptor agonist BW723C86 and the 5-HT1B receptor agonist CGS12066A (10(-9)-10(-5) M, 5-min stimulation) did not activate the JAK/STAT pathway. Treatment with the 5-HT2A receptor antagonist ketanserin (10 nM) inhibited JAK2 activation by 5-HT. Treatment of streptozotocin-induced diabetic rats with ketanserin (5 mg.kg-1.day-1) reduced activation of JAK2 and STAT1 but not STAT3 in endothelium-denuded thoracic aorta in vivo. 5-HT (10(-6) M) treatment resulted in increased cell proliferation and increased DNA synthesis, which were inhibited by the JAK2 inhibitor AG490. Further studies with apocynin, diphenyleneiodonium chloride, catalase, and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK/STAT pathway by 5-HT. Therefore, we conclude that 5-HT activates JAK2, JAK1, and STAT1 via the 5-HT2A receptors in a reactive oxygen species-independent manner under both normal and high glucose conditions.
血清素（5-羟色胺，5-HT）是一种血管收缩剂和促细胞分裂剂，其水平在糖尿病患者中会升高。先前的研究表明，血管平滑肌细胞（VSMC）中存在5-HT2A、5-HT2B和5-HT1B受体。目前尚无关于VSMC中5-HT2B和5-HT1B受体激活JAK/STAT途径以及糖尿病中5-HT信号传导潜在改变的数据。因此，我们测试了以下假设：在正常（5 mM）和高（25 mM）葡萄糖条件下，5-HT在VSMC中差异激活JAK/STAT途径。用5-HT（10⁻⁶ M）处理大鼠VSMC导致JAK2、JAK1和STAT1的时间依赖性激活（约2倍），但不激活STAT3（在5分钟时达到最大值，30分钟时恢复到基线）。5-HT2B受体激动剂BW723C86和5-HT1B受体激动剂CGS12066A（10⁻⁹ - 10⁻⁵ M，5分钟刺激）未激活JAK/STAT途径。用5-HT2A受体拮抗剂酮色林（10 nM）处理可抑制5-HT对JAK2的激活。用酮色林（5 mg·kg⁻¹·天⁻¹）处理链脲佐菌素诱导的糖尿病大鼠可降低体内去内皮胸主动脉中JAK2和STAT1的激活，但不降低STAT3的激活。5-HT（10⁻⁶ M）处理导致细胞增殖增加和DNA合成增加，这被JAK2抑制剂AG490抑制。用阿扑辛、二苯碘鎓氯化物、过氧化氢酶和病毒转染的超氧化物歧化酶进行的进一步研究在两种葡萄糖浓度下对5-HT激活JAK/STAT途径均无影响。因此，我们得出结论，在正常和高葡萄糖条件下，5-HT通过5-HT2A受体以不依赖活性氧的方式激活JAK2、JAK1和STAT1。
