The role of beta-adrenergic receptor signaling in cardioprotection.
The role of beta-adrenergic receptor signaling in cardioprotection.
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发表时间：
2005
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通讯作者：
Haiyan Tong;D. Bernstein;E. Murphy;C. Steenbergen
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作者：
Haiyan Tong;D. Bernstein;E. Murphy;C. Steenbergen
本研究探讨了β 2-肾上腺素能受体（β 2-AR）在心脏保护中的作用。β 2-AR与Gs和Gi蛋白偶联。Gs激活PKA，PKA使受体磷酸化并将β 2-AR偶联从Gs转换为Gi。在20分钟的全脑缺血之前，小鼠心脏灌注30分钟而不处理（对照），用10 nmol/L的异丙肾上腺素（ISO）处理5分钟，然后5分钟冲洗，或用4个循环的5分钟缺血和5分钟再流（PC）预处理。观察左室发展压（LVDP）恢复情况及心肌梗死面积。间歇性ISO治疗改善了缺血后LVDP的恢复（58.5+/-4.8% vs.对照组22.0+/-6.3%），并缩小了梗死面积（31.0+/-2.4% vs.对照组53.0+/-4.6%）。Gi抑制剂百日咳毒素阻断了ISO诱导的缺血后LVDP和梗死面积的改善。为了测试β 2-AR在PC中的作用，我们研究了缺乏β 2-AR（β 2-AR-/-）的小鼠，发现PC对β 2-AR-/-的缺血后LVDP或梗死面积没有影响。为了测试PKA是否是PC和ISO诱导的保护所必需的，心脏用PKA抑制剂PKI和H-89处理。我们发现，PKI和H-89阻断PC和ISO诱导的缺血后LVDP和梗死面积的改善。这些数据显示β 2-AR在心脏保护中的重要作用，并支持预处理涉及β 2-AR偶联从Gs转换为Gi的新假设。
This study examines the role of the beta2-adrenergic receptor (beta2-AR) in cardioprotection. The beta2-AR couples to Gs and Gi proteins. Gs activates PKA, which phosphorylates the receptor and switches beta2-AR coupling from Gs to Gi. Prior to 20 min of global ischemia, mouse hearts were either perfused for 30 min without treatment (control), treated with 10 nmol/L of isoproterenol (ISO) for 5 min followed by 5 min washout, or preconditioned with 4 cycles of 5 min ischemia and 5 min reflow (PC). Recovery of left ventricular developed pressure (LVDP) and infarct size were measured. Intermittent ISO treatment improved post-ischemic recovery of LVDP (58.5+/-4.8% vs. 22.0+/-6.3% in control) and reduced infarct size (31.0+/-2.4% vs. 53.0+/-4.6% in control). The Gi inhibitor pertussis toxin blocked the ISO-induced improvement in postischemic LVDP and infarct size. To test the role of beta2-AR in PC, we studied mice lacking beta2-AR (beta2-AR-/-) and found that PC had no effect on postischemic LVDP or infarct size in beta2-AR-/-. To test whether PKA is required for the PC and ISO-induced protection, hearts were treated with the PKA inhibitors PKI and H-89. We found that PKI and H-89 blocked the PC- and ISO-induced improvement in postischemic LVDP and infarct size. These data show an important role for beta2-AR in cardioprotection and support the novel hypothesis that preconditioning involves switching of beta2-AR coupling from Gs to Gi.