Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts
Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts
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DOI：
10.1152/ajpheart.00878.2012
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发表时间：
2013-05-01
影响因子：
4.8
通讯作者：
Morley, Gregory E.
中科院分区：
文献类型：
--
作者：
Benamer, Najate;Vasquez, Carolina;Morley, Gregory E.
心肌梗塞后，心脏代谢在很长一段时间内保持改变。研究表明，正常心脏的成纤维细胞在培养物中表达 K-ATP 通道。目前尚不清楚梗塞心脏的成纤维细胞是否表达 K-ATP 通道以及这些通道是否有助于疤痕和边界区电生理学。测定从正常心脏 (Fb)、左冠状动脉前降支 (LAD) 结扎大鼠心脏的疤痕 (sMI-Fb) 和远端 (rMI-Fb) 区域分离的成纤维细胞中的 K-ATP 通道亚基表达水平。用膜片钳测定全细胞K-ATP电流密度。在含有和不含有 100 μmol/l 吡那地尔的纯肌细胞培养物和含有成纤维细胞的异细胞培养物中，通过光学测绘测量动作电位持续时间 (APD)。全心光学测绘用于评估 LAD 连接后的 K-ATP 通道活性。吡那地尔激活 sMI-Fb 中的钾电流（50 mV 时为 35.4 +/- 7.5 pA/pF），该钾电流被 10 μmol/l 格列本脲抑制。 sMI-Fb 中 Kir6.2 和 SUR2 转录水平升高。用 Kir6.2 短干扰 RNA 处理可降低 sMI-Fb 中的 K-ATP 电流 (87%)。在与 sMI-Fb 共培养中，吡那地尔治疗可降低 APD (26%)。灌注格列本脲后，LAD 结扎心脏的 APD 值延长。 K-ATP 通道存在于梗塞心脏的疤痕和边缘区的成纤维细胞中。成纤维细胞 K-ATP 通道的激活可以调节急性缺血事件之外的电生理底物。靶向成纤维细胞 K-ATP 通道可能代表一种改变心脏损伤后边界区电生理学的新治疗方法。
Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express K-ATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express K-ATP channels and whether these channels contribute to scar and border zone electrophysiology. K-ATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI-Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell K-ATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 mu mol/l pinacidil. Whole heart optical mapping was used to assess K-ATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 +/- 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 mu mol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased K-ATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. K-ATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast K-ATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast K-ATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury.