Abstract 209: Pharmacological Enhancement of Postconditioning with PAR2 Activation Reduces Reperfusion Injury after Acute Myocardial Infarction
Background: Postconditioning (Postcon), defined as alternating cycles of reperfusion and re-occlusion applied at the immediate onset of reperfusion (R) in experimental and clinical studies reduces infarct size. Protease activated receptor-2 (PAR2) agonists are cardioprotective in an ex vivo myocardial ischemia-R model. Both cardioprotective strategies activate the ERK 1/2 pathway, but the PI3K/ Akt pathway is controversial. This study tested the hypothesis that co-application of Postcon and PAR2 agonist during early R achieves greater infarct size reduction than either intervention alone via the ERK 1/2 pathway in the in vivo rat myocardial ischemia-R model.
Methods: In anesthetized open-chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 hours. Rats were randomly assigned to 9 groups:
Control: no intervention at R;
Postcon: three cycles of 10-s R followed by 10-s re-occlusion were applied during the first min of R;
PAR2 agonist peptide SLIGRL (PAR2 AP) 1 mg/Kg was infused i.v. 5 min before R;
PAR2 AP plus the ERK 1/2 inhibitor PD 98059 (PD, 0.3 mg/Kg) or
PAR2 AP plus the PI3-kinase inhibitor Ly 294002 (Ly, 0.3 mg/Kg) were given 10 min before R;
Postcon plus PD;
Postcon + Ly;
Combination PAR2 AP + Postcon;
PD plus Combination PAR2 AP + Postcon.
Results: Compared to Control, infarct size (TTC) was comparably smaller in both Postcon and PAR2 AP groups (Table⇓). Infarct sparing effects of Postcon or PAR2 AP alone were blocked by ERK1/2 inhibition (PD), but not by PI3 K inhibition (LY). The combination of PAR2 AP + Postcon further reduced infarct size compared to either intervention alone, which was abolished by ERK 1/2 inhibitor PD.
Conclusions: Infarct size reduction by Postcon or PAR2 AP alone is enhanced by their simultaneous combination at R, potentially by stimulating the ERK 1/2 pathway, but not the PI3K pathway.