The role of beta-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.
Tong
Haiyan
H
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Bernstein
Daniel
D
Murphy
Elizabeth
E
Steenbergen
Charles
C
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000037:antagonists & inhibitors / Q000502:physiology; D007511:Ischemia; D019157:Ischemic Preconditioning, Myocardial; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D037342:Pertussis Toxin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D002316:Cardiotonic Agents; D047428:Protein Kinase Inhibitors; D018343:Receptors, Adrenergic, beta-2; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol