Abstract 19839: Annexin-a1 Tripeptide is Cardioprotective in Several Preclinical Models of Ischemia-Reperfusion Through Resolution of Myocardial Inflammation
Background: Annexin A1 is a glucocorticoid-regulated protein that plays a pivotal role as an endogenous regulator of the inflammatory response, with many of its anti-inflammatory properties retained by the N-terminal peptides. Using in vitro and in vivo models of myocardial ischemia-reperfusion (I/R) under both normo- and hyperglycemic conditions, we tested the hypothesis that a novel annexin A1 tripeptide (ANXA1sp) exerts cardioprotective effects through resolution of myocardial inflammation.
Methods: In vitro simulated I/R: Adult rat ventricular cardiomyocytes were incubated in normal or high glucose (25mM), with and without ANXA1sp (30 μM) for 24h, subjected to 2h oxygen-glucose deprivation, followed by 24h reoxygenation in either normo- or hyperglycemic medium. Rat I/R: SD rats underwent 75 min of mild hypothermic cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA) in 4 groups: normo- and hyperglycemic (20mM) CA, each treated with ANXA1sp (3mg/kg) or vehicle. Pig I/R: Yorkshire pigs subjected to 180 min of mild hypothermic CPB with 60 min of CA received ANXA1sp (4mg/kg) or vehicle. Efficacy endpoints assessed at 24h post-reoxygenation (ARVC), 24h (rat) and 6h (pig) post-reperfusion include markers of myonecrosis, apoptosis, myocardial inflammation, leukocyte extravasation, and pump function.
Results: ANXA1sp consistently attenuated myocardial I/R injury under both glycemic conditions, which correlated with reduced activation of NF-κB pathway (Figure). Peptide treated pigs further demonstrated improved myocardial energetics and hemodynamics, none requiring inotropic or vasopressor support, which was substantial in all control animals.
Conclusions: Using a translational approach and robust efficacy endpoints, we report that ANXA1sp elicits cardioprotection in vitro and in small and large animal models of surgical I/R. The effects are not blunted by hyperglycemia and involve attenuation of myocardial inflammation.
- © 2010 by American Heart Association, Inc.