Tong Haiyan, Bernstein Daniel, Murphy Elizabeth, Steenbergen Charles
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
FASEB J. 2005 Jun;19(8):983-5. doi: 10.1096/fj.04-3067fje. Epub 2005 Mar 31.
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.
本研究探讨β2-肾上腺素能受体（β2-AR）在心脏保护中的作用。β2-AR与Gs和Gi蛋白偶联。Gs激活蛋白激酶A（PKA），PKA使受体磷酸化并将β2-AR的偶联从Gs转换为Gi。在全心缺血20分钟之前，对小鼠心脏进行如下处理：未处理灌注30分钟（对照）；用10 nmol/L异丙肾上腺素（ISO）处理5分钟，随后冲洗5分钟；或用4个循环的5分钟缺血和5分钟再灌注进行预处理（PC）。测量左心室舒张末压（LVDP）的恢复情况和梗死面积。间歇性ISO处理改善了缺血后LVDP的恢复（58.5±4.8%，对照为22.0±6.3%）并减小了梗死面积（31.0±2.4%，对照为53.0±4.6%）。Gi抑制剂百日咳毒素阻断了ISO诱导的缺血后LVDP改善和梗死面积减小。为了测试β2-AR在PC中的作用，我们研究了缺乏β2-AR的小鼠（β2-AR-/-），发现PC对β2-AR-/-小鼠缺血后的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，用PKA抑制剂PKI和H-89处理心脏。我们发现PKI和H-89阻断了PC和ISO诱导的缺血后LVDP改善和梗死面积减小。这些数据表明β2-AR在心脏保护中起重要作用，并支持了预处理涉及β2-AR偶联从Gs转换为Gi这一新假说。
