Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis
Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis
复制标题
丹参酮 IIA 磺酸钠通过 PKG-PPAR-gamma 信号轴抑制缺氧诱导的肺动脉平滑肌细胞 SOCE 增强
DOI：
10.1152/ajpcell.00252.2015
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发表时间：
2016-07-01
影响因子：
5.5
通讯作者：
Sun, Dejun
中科院分区：
文献类型：
--
作者：
Jiang, Qian;Lu, Wenju;Sun, Dejun
本实验室之前的研究表明，丹参酮IIA磺酸钠（STS）通过下调瞬时受体电位规范蛋白（TRPC）的表达，抑制储存-操作Ca2+通道（SOCC）的储存-操作Ca2+进入（SOCE），而TRPC有助于SOCC的形成（王娟，姜强，万玲，杨凯，张颖，陈颖，王娥，来宁，赵玲，蒋海，孙燕，钟宁，然鹏，卢伟，Am J呼吸细胞学报，48:125-134,2013）。然而，STS抑制SOCE和下调TRPC的详细分子机制在很大程度上仍然未知。我们之前的研究表明，在缺氧条件下，蛋白激酶G （PKG）和过氧化物酶体增殖激活受体γ (ppar - γ)信号轴的抑制导致TRPC上调（王娟，杨凯，徐丽，张燕，赖宁，蒋华，张燕，钟宁，冉平，卢文安，J .呼吸细胞学报，49:231-240,2013）。这表明，以恢复这一信号通路为目标的策略可能是治疗肺动脉高压的有效策略。在本研究中，我们的研究结果表明，STS治疗可以有效预防缺氧介导的大鼠肺动脉远端平滑肌细胞（PASMCs）和肺动脉远端pkg - ppar - γ信号轴的抑制。STS治疗的这些作用被PKG或ppar - γ的药理抑制或特异性小干扰RNA敲除所阻断。此外，靶向ppar - γ激动剂显著增强了STS的有益作用。这些结果综合表明，STS治疗可以通过靶向和恢复pasmc中缺氧抑制的pkg - ppar - γ信号通路，阻止缺氧介导的细胞内钙稳态和细胞增殖的增加。
Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125-134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231-240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia-mediated inhibition of the PKG-PPAR-gamma signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-gamma. Moreover, targeted PPAR-gamma agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-gamma signaling pathway in PASMCs.