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首页> 外文期刊>Drug Design, Development and Therapy >Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition
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Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition

机译：给药时间和KV7子信道对KV7通道抑制的心脏保护疗效的影响

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Purpose: The mechanism of cardioprotection by Kv7.1– 5 (KCNQ1-5) channels inhibition by XE991 is unclear. We examined the impact of administration time on the cardioprotective efficacy of XE991, the involvement of key pro-survival kinases, and the importance of the Kv7 subchannels. Methods: Isolated perfused rat hearts were divided into five groups: 1) vehicle, 2) pre-, 3) post- or 4) pre- and post-ischemic administration of XE991 or 5) chromanol 293B (Kv7.1 inhibitor) followed by infarct size quantification. HL-1 cells undergoing simulated ischemia/reperfusion were exposed to either a) vehicle, b) pre-, c) per-, d) post-ischemic administration of XE991 or pre-, per- and post-ischemic administration of e) XE991, f) Chromanol 293B or g) HMR1556 (Kv7.1 inhibitor). HL-1 cell injury was evaluated by propidium iodide/Hoechst staining. Pro-survival kinase activation of Akt, Erk and STAT3 in XE991-mediated HL-1 cell protection was evaluated using phosphokinase inhibitors. Kv7 subtype expression was examined by RT-PCR and qPCR. Results: XE991, but not Chromanol 293B, reduced infarct size and improved hemodynamic recovery in all isolated heart groups. XE991 protected HL-1 cells when administered during simulated ischemia. Minor activation of the survival kinases was observed in cells exposed to XE991 but pharmacological inhibition of kinase activation did not reduce XE991-mediated protection. Kv7 subchannels 1– 5 were all present in rat hearts but predominately Kv7.1 and Kv7.4 were present in HL-1 cells and selective Kv7.1 did not reduce ischemia/reperfusion injury. Conclusion: The cardioprotective efficacy of XE991 seems to depend on its presence during ischemia and early reperfusion and do not rely on RISK (p-Akt and p-Erk) and SAFE (p-STAT3) pathway activation. The protective effect of XE991 seems mainly mediated through the Kv7.4 subchannel.
机译：目的：通过XE991抑制KV7.1-5（KCNQ1-5）通道抑制的心脏保护机制尚不清楚。我们研究了给药时间对XE991的心脏保护疗效的影响，关键促生物激酶的累及，以及KV7子信道的重要性。方法：分离灌注大鼠心脏分为五组：1）载体，2）前，3）后XE991或5）缺血后缺血给药后和后缺血给药，其次是作者：XE991或5）Chromanol 293b（Kv7.1抑制剂）。梗塞尺寸量化。经历模拟缺血/再灌注的HL-1细胞暴露于A）载体，B）预见，C）Per-，D）XE991或e）Xe991的缺血介导的缺血给药后缺血给药XE991 F）Chromanol 293b或g）HMR1556（Kv7.1抑制剂）。通过碘化钛/ Hoechst染色评估HL-1细胞损伤。使用磷氨基酶抑制剂评估XE991介导的HL-1细胞保护中AKT，ERK和STAT3的Pro-survival激酶活化。通过RT-PCR和QPCR检查KV7亚型表达。结果：XE991，但不是Chromanol 293b，减少梗塞大小，并在所有孤立的心脏群中改善了血流动力学恢复。 XE991在模拟缺血期间施用时受保护的HL-1细胞。在暴露于XE991的细胞中观察到存活激酶的微细活化，但激酶活化的药理学抑制不会降低XE991介导的保护。 KV7子信道1-5全部存在于大鼠心中，但主要是KV7.1和KV7.4在HL-1细胞中存在，选择性KV7.1并未降低缺血/再灌注损伤。结论：XE991的心脏保护疗效似乎取决于其在缺血和早期再灌注过程中的存在，并且不依赖风险（p-akt和p-erk）和安全（p-stat3）途径激活。 XE991的保护作用似乎主要通过KV7.4子信道介导。

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