Differential sensitivities of the vascular K(ATP) channel to various PPAR activators.
Differential sensitivities of the vascular K(ATP) channel to various PPAR activators.
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DOI：
10.1016/j.bcp.2013.02.039
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发表时间：
2013-05-15
影响因子：
5.8
通讯作者：
Jiang, Chun
中科院分区：
文献类型：
--
作者：
Wang, Yingji;Yu, Lei;Cui, Ningren;Jin, Xin;Zhu, Daling;Jiang, Chun
几种过氧化物酶体增殖物激活受体（ppar）激动剂目前用于治疗代谢紊乱，包括糖尿病。我们最近发现其中一种药物罗格列酮抑制血管atp敏感的K+ (KATP)通道，并通过β-肾上腺素能受体激动剂影响冠状动脉舒张。在这里，我们展示了各种PPAR激动剂对通道抑制的证据，这些信息可能有助于寻找具有更少心血管副作用的新治疗药物和针对Kir6.1亚基的更具选择性的KATP通道阻滞剂。这些PPAR激动剂的结构比较可能有助于深入了解通道抑制的关键化学基团。Kir6.1/SUR2B通道在HEK293细胞中表达，并在全细胞电压箝位下进行了研究。Kir6.1/SUR2B通道被几种效价类似或高于罗格列酮的PPARγ激动剂强烈抑制，而其他PPARγ激动剂几乎没有抑制该通道。Kir6.1/SUR2B通道也被中间效价的PPARα和PPARβ/δ激动剂抑制。通道抑制所必需的结构似乎包括与芳香环或呋喃环相连的噻唑。侧基（如小脂肪链）的加入增加了通道抑制的效力，而芳香环的加入则降低了通道抑制的效力。这些结果表明，具有弱KATP通道抑制作用的PPARγ激动剂可能是潜在的候选治疗药物，而具有强通道抑制作用的PPARγ激动剂可能用作选择性KATP通道阻断剂。PPAR激动剂的结构信息可能有助于开发心血管副作用较小的新治疗方式。
Several agonists of the peroxisome proliferator-activated receptors (PPARs) are currently used for the treatment of metabolic disorders including diabetes. We have recently shown that one of them, Rosiglitazone, inhibits the vascular ATP-sensitive K+ (KATP) channel and compromises the coronary vasodilation by the β-adrenoceptor agonist. Here, we show evidence for the channel inhibition by various PPAR agonists, information that may be useful for finding new therapeutical agents with less cardiovascular side-effects and more selective KATP channel blockers targeting at the Kir6.1 subunit. Structural comparison of these PPAR agonists may shed insight into the critical chemical groups for the channel inhibition. Kir6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell voltage clamp. The Kir6.1/SUR2B channel was strongly inhibited by several PPARγ agonists with potencies similar to, or higher than, that of Rosiglitazone, while other PPARγ agonists barely inhibited the channel. The Kir6.1/SUR2B channel was also inhibited by PPARα and PPARβ/δ agonists with intermediate potencies. The structure necessary for the channel inhibition appears to include the thiazole linked to an aromatic or furan ring. Additions of side groups such as small aliphatic chain increased the potency for channel inhibition, while additions of aromatic rings reduced it. These results indicate that the PPARγ agonists with weak KATP channel inhibition may be potential candidates as therapeutical agents, and those with strong channel inhibition may be used as selective KATP channel blockers. The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects.
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DOI：
10.1152/ajpregu.00047.2007
发表时间：
2007-07-01
影响因子：
2.8
作者：
Shi, Weiwei;Cui, Ningren;Jiang, Chun
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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