Nobiletin, a dietary phytochemical, inhibits vascular smooth muscle cells proliferation via calcium-mediated c-Jun N-terminal kinases pathway
Nobiletin, a dietary phytochemical, inhibits vascular smooth muscle cells proliferation via calcium-mediated c-Jun N-terminal kinases pathway
复制标题
DOI：
10.1016/j.ejphar.2009.05.025
复制
发表时间：
2009-08-01
影响因子：
5
通讯作者：
Wu, Yu-Qing
中科院分区：
文献类型：
--
作者：
Zhou, Cheng-Hua;Wu, Xiao-Hong;Wu, Yu-Qing
膳食类黄酮已被证明可以降低心血管疾病的风险，但其潜在的分子机制尚不清楚。本研究旨在探讨柑橘皮中提取的多甲氧基黄酮类化合物--陈皮素对血管平滑肌细胞（VSMCs）增殖的影响及其机制。采用MTT法和[H-3]胸苷掺入法检测细胞增殖。Western blotting检测细胞外信号调节激酶1/2（ERK 1/2）、c-Jun N末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）活性。[Ca2+]（i）通过激光扫描共聚焦显微镜测量。我们的研究结果表明，血管紧张素II诱导的VSMCs增殖被抑制的nobilectin。而对ERK 1/2和p38 MAPK无影响，nobilectin显著抑制血管紧张素II诱导的JNK激活。JNK抑制剂蒽[1-9-cd]吡唑-6（2 H）-酮（SP 600125）可减少血管紧张素II诱导的[H-3]胸苷掺入。Nobiletin还减弱了血管紧张素II诱导的细胞内Ca 2+动员和细胞外Ca 2+内流。此外，BAPTA-AM对细胞内Ca ~（2+）的螯合作用、EGTA对细胞外Ca ~（2+）的螯合作用或维拉帕米对L型Ca ~（2+）通道的阻断作用均能抑制血管紧张素II诱导的JNK激活。这些结果表明，nobilipine对血管紧张素II诱导的VSMCs增殖的预防作用部分归因于其对VSMCs中Ca 2+依赖性JNK激活的抑制作用。因此，抑制JNK的诺贝尔碱可能意味着其有用的治疗心血管疾病相关的VSMCs的生长。(C)2009 Elsevier B. V.保留所有权利。
Dietary flavonoids have been shown to reduce risk of cardiovascular disease, but the underlying molecular mechanisms are not known. The objective of this study was to investigate the effect of nobiletin, a dietary phytochemical belonging to polymethoxy flavonoid from the peel of Citrus fruit, on vascular smooth muscle cells (VSMCs) proliferation and its mechanisms. VSMCs proliferation was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide (MTT) and [H-3]thymidine incorporation assay. The activity of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK) were determined by western blotting. [Ca2+](i) was measured by laser scanning confocal microscopy. Our results showed that angiotensin II-induced VSMCs proliferation was inhibited by nobiletin. While no effect on ERK1/2 and p38 MAPK, nobiletin markedly inhibited angiotensin II-induced activation of JNK. Anthra[1-9-cd]pyrazol-6(2H)-one (SP600125), an inhibitor of JNK, decreased the [H-3]thymidine incorporation induced by angiotensin II. Nobiletin also attenuated both the intracellular Ca2+ mobilization and the extracellular Ca2+ influx induced by angiotensin II. Furthermore, intracellular Ca2+ chelation by BAPTA-AM, extracellular Ca2+ chelation by EGTA or blockade of L-type Ca2+ channel with verapamil inhibited angiotensin II-induced JNK activation. These findings suggest that the preventing effect of nobiletin on angiotensin II-induced VSMCs proliferation is attributed, in part, to its inhibitory effect on Ca2+-dependent JNK activation in VSMCs. Thus, inhibition of JNK by nobiletin may imply its usefulness for the treatment of cardiovascular diseases relevant to VSMCs growth. (C) 2009 Elsevier B.V. All rights reserved.