Hemichannels in cardiomyocytes open transiently during ischemia and contribute to reperfusion injury following brief ischemia
Hemichannels in cardiomyocytes open transiently during ischemia and contribute to reperfusion injury following brief ischemia
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DOI：
10.1152/ajpheart.00022.2007
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发表时间：
2007-09-01
影响因子：
4.8
通讯作者：
Yoshida, Ken-Ichi
中科院分区：
文献类型：
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作者：
Shintani-Ishida, Kaori;Uemura, Koichi;Yoshida, Ken-Ichi
本研究的目的是探讨半通道活性在体外模拟缺血[氧-葡萄糖剥夺（OGD）]过程中的变化以及半通道在新生大鼠心肌细胞缺血-再灌注损伤中的作用。染料摄取试验表明，半通道开放的OGD进展，1小时后达到峰值，然后关闭，返回到前OGD状态后2小时的OGD。半通道阻断剂（氯化镧和连接蛋白43模拟肽，Gap 26）抑制OGD 1小时后的染料摄取增加。在OGD过程中，细胞内Ca 2+浓度（[Ca 2 +]（i））在1h后开始增加，2 h后达到几微摩尔。在OGD 1 h后，Gap 26抑制半通道活性和[Ca 2 +]（i）的增加。与此相反，丹曲林[一种内（肌）质网Ca 2+释放抑制剂]抑制[Ca 2 +]i的增加，但不抑制半通道活性。在OGD 2小时后，2 '，4'-二氯苯扎米尔和丹曲林的联合给药将[Ca 2 +]（i）降低至< 1 μ M，并将半通道活性增加至OGD 1小时后达到的水平。模拟缺血再灌注，诱导1小时的OGD，然后2小时的恢复，降低细胞活力的54%的控制水平。向OGD培养基中添加Gap 26将存活率提高至对照水平的80%。总之，本研究表明：1）半通道在OGD期间短暂打开，2）半通道的关闭（但不是其打开）受OGD期间[Ca 2 +]（i）增加的调节，以及3）开放的半通道在从OGD恢复期间有助于细胞损伤。
The aim of this study was to investigate changes in hemichannel activity during in vitro simulated ischemia [oxygen-glucose deprivation (OGD)] and the contribution of hemichannels to ischemia-reperfusion injury in rat neonatal cardiomyocytes. Dye uptake assays showed that hemichannels opened as OGD progressed, peaking after 1 h, and then closed, returning to the pre-OGD state after 2 h of OGD. The increase in dye uptake after 1 h of OGD was inhibited by hemichannel blockers ( lanthanum chloride and a connexin 43 mimetic peptide, Gap26). During OGD, intracellular Ca2+ concentration ([Ca2+](i)) began to increase after 1 h and reached several micromolar after 2 h. After 1 h of OGD, Gap26 inhibited the increases in hemichannel activity and [Ca2+](i). In contrast, dantrolene [ an endo(sarco)plasmic reticulum Ca2+ release inhibitor] suppressed the increase in [Ca2+]i, but not in hemichannel activity. After 2 h of OGD, the combined administration of 2', 4'-dichlorobenzamil and dantrolene reduced [Ca2+](i) to < 1 mu M and increased hemichannel activity to the level attained after 1 h of OGD. Simulated ischemia-reperfusion, induced by 1 h of OGD followed by 2 h of recovery, reduced cell viability to 54% of the control level. The addition of Gap26 to OGD medium improved viability to 80% of the control level. In conclusion, this study demonstrated that 1) hemichannels open transiently during OGD, 2) closure of hemichannels, but not their opening, is regulated by an increase in [Ca2+](i) during OGD, and 3) open hemichannels contribute to cell injury during recovery from OGD.