Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cell Signaling

Background:

• Pharmacological preconditioning protects the heart via signaling pathways.
• Acetylcholine preconditioning involves phosphatidylinositol 3-kinase (PI3-K) and epidermal growth factor receptor (EGFR) transactivation.
• This pathway involves reactive oxygen species (ROS) generation and Src kinase.

Purpose of the Study:

• To investigate whether physiological triggers, bradykinin and opioid agonists, signal through EGFR.
• To elucidate the signaling mechanisms of bradykinin and opioid-induced cardioprotection.

Main Methods:

• Isolated cardiomyocytes and whole rabbit hearts were used.
• Experiments involved measuring ROS production, infarct size, and protein phosphorylation.
• Pharmacological inhibitors targeting metalloproteinase (MPI), EGFR (AG1478), Src kinase (PP2), and PI3-K (wortmannin) were employed.

Main Results:

• The opioid agonist DADLE increased ROS production and provided infarct protection, effects blocked by metalloproteinase inhibitors and EGFR antagonist AG1478, indicating EGFR transactivation.
• DADLE also increased Akt and ERK phosphorylation, blocked by AG1478.
• Bradykinin increased ROS production and provided infarct protection, but these effects were independent of EGFR transactivation (MPI, CRM-197 resistant). However, bradykinin's effects were blocked by Src kinase inhibitor PP2 and PI3-K inhibitor wortmannin, and it increased Akt/ERK phosphorylation independently of EGFR.

Conclusions:

• Opioid preconditioning, unlike bradykinin, signals through EGFR transactivation, involving metalloproteinase-mediated release of HB-EGF.
• Both bradykinin and opioids activate Src kinase and PI3-K, crucial for their cardioprotective effects.
• Bradykinin mediates cardioprotection independently of EGFR transactivation, highlighting distinct signaling pathways for different preconditioning agents.