The role of β-adrenergic receptor signaling in cardioprotection

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.