Title of article :
Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways
Author/Authors :
Michael V. Cohen، نويسنده , , Sebastian Philipp، نويسنده , , Thomas Krieg، نويسنده , , Lin Cui ، نويسنده , , Atsushi Kuno، نويسنده , , Viktoriya Solodushko، نويسنده , , James M. Downey، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2007
Pages :
10
From page :
842
To page :
851
Abstract :
We previously reported that pharmacological preconditioning of rabbit hearts with acetylcholine involves activation of phosphatidylinositol 3-kinase (PI3-K) through transactivation of the epidermal growth factor receptor (EGFR). Transactivation is thought to be initiated by cleavage of membrane-bound pro-heparin-binding EGF-like growth factor (HB-EGF) by a membrane metalloproteinase thus releasing HB-EGF which binds to the EGFR. This pathway leads to redox signaling with the generation of reactive oxygen species (ROS) by mitochondria. We tested whether preconditioningʹs physiological triggers, bradykinin and opioid, also signal through the EGFR. Both bradykinin and the synthetic δ-opioid agonist DADLE increased ROS production in isolated cardiomyocytes by approximately 50%. DADLEʹs effect was abrogated by either metalloproteinase inhibitor III (MPI) or the diphtheria toxin mutant CRM-197 which blocks heparin-binding EGF shedding indicating that DADLE signals through EGFR transactivation. MPI also blocked DADLEʹs infarct-sparing effect in whole hearts. Additionally, blocking Src kinase (a component of the EGFRʹs signaling complex) with PP2 or PI3-K with wortmannin blocked DADLEʹs effect on cardiomyocyte ROS production and PP2 blocked DADLEʹs salvage of ischemic myocardium. Finally, DADLE increased phosphorylation of Akt and extracellular signal-regulated protein kinases (ERK) 1/2 in left ventricular myocardium, and this increase was blocked by the EGFR antagonist AG1478. On the other hand, neither MPI nor CRM-197 prevented bradykinin from increasing ROS production, and MPI did not affect bradykininʹs infarct-sparing effect in intact hearts. Conversely, both PP2 and wortmannin blocked bradykininʹs effect on ROS generation and also aborted bradykininʹs cardioprotective effect in intact hearts. While bradykinin also increased phosphorylation of Akt and ERK in myocardium, that increase was not affected by AG1478. Hence bradykinin, unlike acetylcholine or opioid, does not transactivate EGFR, although all 3 agonists do signal through Src and PI3-K.
Keywords :
bradykinin , epidermal growth factor , opioids , Preconditioning , transactivation
Journal title :
Journal of Molecular and Cellular Cardiology
Serial Year :
2007
Journal title :
Journal of Molecular and Cellular Cardiology
Record number :
530112
Link To Document :
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