Tanshinone IIA inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway.
Tanshinone IIA inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway.
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丹参酮 IIA 通过 Akt/Skp2/p27 相关途径抑制缺氧诱导的肺动脉平滑肌细胞增殖
DOI：
10.1371/journal.pone.0056774
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li ZC
中科院分区：
文献类型：
--
作者：
Luo Y;Xu DQ;Dong HY;Zhang B;Liu Y;Niu W;Dong MQ;Li ZC
我们先前研究表明丹参酮IIA部分通过减轻肺动脉重构来减轻缺氧性肺动脉高压。低氧诱导的肺动脉平滑肌细胞（PASMCs）增殖是导致肺动脉重构的主要原因之一，本研究旨在探讨丹参酮IIA对低氧诱导的PASMCs增殖的影响及其机制。从雄性Sprague-Dawley大鼠中分离PASMCs，并在常氧（21%）或缺氧（3%）条件下培养。用3 -（4，5 -二甲基噻唑-2-基）-2，5-二苯基四氮唑溴化物法和细胞计数法测定细胞增殖。流式细胞仪检测细胞周期。Western blot和/或RT-PCR分别检测p27、Skp-2的表达和Akt的磷酸化。结果表明，丹参酮IIA可明显抑制缺氧诱导的PASMCs增殖，并呈浓度依赖性，使细胞阻滞于G1/G 0期。丹参酮Ⅱ A可通过减缓p27蛋白的降解来逆转缺氧诱导的PASMCs细胞周期蛋白依赖性激酶抑制剂p27蛋白的减少。用特异性siRNA敲除p27后，丹参酮IIA的抗增殖作用消失。此外，丹参酮IIA抑制缺氧诱导的S期激酶相关蛋白2（Skp 2）的增加和Akt的磷酸化，这两者都参与了p27蛋白的降解。丹参酮IIA可显著上调缺氧诱导的HPH大鼠肺动脉p27蛋白表达减少，下调缺氧诱导的Skp 2蛋白表达增加。因此，我们推测丹参酮IIA抑制缺氧诱导的PASMCs增殖可能是通过Akt/Skp 2相关途径减缓缺氧诱导的p27降解，使细胞阻滞于G1/G 0期。新的信息部分解释了丹参酮IIA对HPH肺动脉重构的抗作用。
We previously showed that tanshinone IIA ameliorated the hypoxia-induced pulmonary hypertension (HPH) partially by attenuating pulmonary artery remodeling. The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the major causes for pulmonary arterial remodeling, therefore the present study was performed to explore the effects and underlying mechanism of tanshinone IIA on the hypoxia-induced PASMCs proliferation. PASMCs were isolated from male Sprague-Dawley rats and cultured in normoxic (21%) or hypoxic (3%) condition. Cell proliferation was measured with 3 - (4, 5 - dimethylthiazal - 2 - yl) - 2, 5 - diphenyltetrazoliumbromide assay and cell counting. Cell cycle was measured with flow cytometry. The expression of of p27, Skp-2 and the phosphorylation of Akt were measured using western blot and/or RT-PCR respectively. The results showed that tanshinone IIA significantly inhibited the hypoxia-induced PASMCs proliferation in a concentration-dependent manner and arrested the cells in G1/G0-phase. Tanshinone IIA reversed the hypoxia-induced reduction of p27 protein, a cyclin-dependent kinase inhibitor, in PASMCs by slowing down its degradation. Knockdown of p27 with specific siRNA abolished the anti-proliferation of tanshinone IIA. Moreover, tanshinone IIA inhibited the hypoxia-induced increase of S-phase kinase-associated protein 2 (Skp2) and the phosphorylation of Akt, both of which are involved in the degradation of p27 protein. In vivo tanshinone IIA significantly upregulated the hypoxia-induced p27 protein reduction and downregulated the hypoxia-induced Skp2 increase in pulmonary arteries in HPH rats. Therefore, we propose that the inhibition of tanshinone IIA on hypoxia-induce PASMCs proliferation may be due to arresting the cells in G1/G0-phase by slowing down the hypoxia-induced degradation of p27 via Akt/Skp2-associated pathway. The novel information partially explained the anti-remodeling property of tanshinone IIA on pulmonary artery in HPH.
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DOI：
10.1155/2012/716459
发表时间：
2012
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
--
作者：
Shang Q;Xu H;Huang L
通讯作者：
Huang L
丹参酮 IIA 在体外和体内诱导胃癌生长抑制和凋亡
影响因子：
4.2
作者：
Chen, Jian;Shi, Dong-Yun;Zhong, Liang
通讯作者：
Zhong, Liang
影响因子：
9.2
作者：
Tsvetkov, LM;Yeh, KH;Zhang, H
通讯作者：
Zhang, H
影响因子：
12.8
作者：
Sung, HJ;Choi, SM;An, KS
通讯作者：
An, KS
影响因子：
56.9
作者：
Hengst, L;Reed, SI
通讯作者：
Reed, SI