Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells
Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells
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DOI：
10.1038/emm.2007.30
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发表时间：
2007-06-30
影响因子：
12.8
通讯作者：
Chung, Hun-Taeg
中科院分区：
文献类型：
--
作者：
Pae, Hyun-Ock;Jeong, Gil-Saeng;Chung, Hun-Taeg
在血管平滑肌细胞（VSMC）中，血红素加氧酶-1（HO-1）的诱导主要通过其上调细胞周期蛋白依赖性激酶抑制剂p21（WAF 1/CIP 1）来赋予血管针对细胞增殖的保护作用，该抑制剂参与细胞增殖的负调节。在本研究中，我们研究了植物化学物质姜黄素及其代谢产物四氢姜黄素是否可以诱导HO-1表达和抑制大鼠VSMCs的生长，如果是这样，它们的抗增殖作用是否可以通过HO-1表达介导。在无毒浓度下，具有两个迈克尔反应受体的姜黄素通过将核转录因子E2相关因子-2（Nrf 2）转运到细胞核中激活抗氧化反应元件（ARE）来诱导HO-1表达，并抑制5%FBS触发的VSMC生长。以剂量依赖性方式。相反，缺乏迈克尔反应受体的四氢姜黄素对HO-1表达、ARE激活和VSMC生长抑制没有影响。姜黄素对VSMCs的抗增殖作用伴随着p21（WAF 1/CIP 1）表达的增加。当细胞与HO抑制剂锡原卟啉共孵育时，姜黄素对VSMC生长和p21 WAF 1/CIP 1表达的抑制部分但不完全消除。在人主动脉平滑肌细胞（HASMCs）中，姜黄素还通过HO-1依赖性方式抑制TNF-α触发的生长并增加p21（WAF 1/CIP 1）表达。我们的研究结果表明，姜黄素有能力诱导HO-1的表达，大概是通过Nrf 2依赖的ARE激活，在大鼠VSMC和HASMCs，并提供证据表明，姜黄素的抗增殖作用是相当大的连接到它的能力，以诱导HO-1的表达。
In vascular smooth muscle cells (VSMCs), induction of the heme oxygenase-1 (HO-1) confers vascular protection against cellular proliferation mainly via its up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) that is involved in negative regulation of cellular proliferation. In the present study, we investigated whether the phytochemical curcumin and its metabolite tetrahydrocurcumin could induce HO-1 expression and growth inhibition in rat VSMCs and, if so, whether their antiproliferative effect could be mediated via HO-1 expression. At non-toxic concentrations, curcumin possessing two Michael-reaction acceptors induced HO-1 expression by activating antioxidant response element (ARE) through translocation of the nuclear transcription factor E2-related factor-2 (Nrf2) into the nucleus and also inhibited VSMC growth triggered by 5% FBS in a dose-dependent manner. In contrast, tetrahydrocurcumin lacking Michael-reaction acceptor showed no effect on HO-1 expression, ARE activation and VSMC growth inhibition. The antiproliferative effect of curcumin in VSMCs was accompanied by the increased expression of p21(WAF1/CIP1). Inhibition of VSMC growth and expression of p21WAF1/CIP1 by curcumin were partially, but not completely, abolished when the cells were coincubated with the HO inhibitor tin protoporphyrin. In human aortic smooth muscle cells (HASMCs), curcumin also inhibited growth triggered by TNF-alpha and increased p21(WAF1/CIP1) expression via HO-1-dependent manner. Our findings suggest that curcumin has an ability to induce HO-1 expression, presumably through Nrf2-dependent ARE activation, in rat VSMCs and HASMCs, and provide evidence that the antiproliferative effect of curcumin is considerably linked to its ability to induce HO-1 expression.