Abstract P285: Impaired Recovery of Left Ventricular Function After Acute Myocardial Reperfusion Injury Is Rescued by the Anti-inflammatory Peptide Annexin-A1 ex Vivo

Abstract

The glucocorticoid-regulated protein annexin-A1 (ANX-A1) is a key effector molecule of anti-inflammatory glucocorticoid actions. We have shown that the N-terminal derived peptide ANX-A1(2–26) preserves cardiomyocyte viability after metabolic inhibition in vitro. Our hypothesis was that ANX-A1 preserves the myocardium post-ischemic injury. ANX-A1(2–26)(0.3μM) prevented adult rat cardiomyocyte injury, whether present for hypoxia-reoxygenation (LDH release reduced from 4.1±0.7- to 1.1±0.2-fold n=11 P<0.001) or only on reoxygenation (LDH release reduced to 1.4±0.4-fold n=11, P<0.001). Similar protection at both time points was also evident on cardiomyocyte viability (trypan blue exclusion). The recovery of post-ischemic left ventricular (LV) function in intact rodent hearts was also protected. After 20mins reperfusion, the recovery of LV developed pressure (LVDP) remained significantly impaired in untreated rat hearts (47±5% baseline, n=11) whereas addition of ANX-A1(2–26)(0.3μM) on reperfusion improved LVDP recovery (to 66±7% baseline, n=13, p<0.05). Phosphorylation of both Akt (1.9±0.2-fold, P<0.05) and phospholamban (3.4±0.4-fold, P<0.05) was also enhanced by ANX-A1(2–26). Similar ANX-A1(2–26)-induced rescue of LV function was observed in mouse hearts after acute myocardial reperfusion injury (57±7% of baseline, n=11 untreated hearts vs 78±8% baseline, n=6 ANX-A1(2–26)-treated hearts, p<0.05). ANX-A1(2–26) cardioprotection was associated with attenuated cardiac enzyme release (LDH, CK) and Akt phosphorylation (3.1±0.8-fold, P<0.005). In contrast, deficiency of endogenous ANX-A1 further exacerbated recovery of post-ischemic LV function, across LVDP (to 29±4% baseline, P<0.001), LV end-diastolic pressure (to 5.5±1.0-fold baseline, P<0.001), LV+dP/dt (to 33±4% baseline, P<0.001), LV-dP/dt (to 36±4% baseline, P<0.001) and rate-pressure product (to 24±4% baseline, P<0.001). This is the first evidence that ANX-A1 or its mimetic ANX-A1(2-26) preserve post-ischemic recovery of LV function. ANX-A1 is thus an endogenous regulator of LV function. Furthermore, ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of reperfusion injury.