Effect of Acetylsalicylic Acid on Nuclear Factor-κB Activation and on Late Preconditioning Against Infarction in the Myocardium

Abstract

Nuclear factor-kappaB (NF-kappaB) plays an essential role in the intracellular signal transduction of the second window of protection (SWOP). Acetylsalicylic acid (ASA) blocks NF-kappaB-dependent gene activation in leukocytes and endothelial cells through preventing phosphorylation and subsequent degradation of the inhibitor IkappaB-alpha. This study investigated the effect of ASA on the late phase of ischemic preconditioning (PC) against myocardial infarction and on the activation of NF-kappaB in the preconditioned myocardium. Conscious rabbits were subjected to 4 cycles of 5 minutes of coronary occlusion and 5 minutes of reperfusion together with 3 different doses of ASA (5 mg/kg; 25 mg/kg; 130 mg/kg). After 30 minutes of reperfusion we determined the activation of NF-kappaB with an electrophoretic mobility shift assay (EMSA). Twenty-four hours later, after 30 minutes of test ischemia, we performed infarct size analysis using triphenyltetrazolium-chloride (TTC) staining. Neither 5 mg/kg (antithrombotic dose) nor 25 mg/kg (analgesic/antipyretic dose) of ASA interfered with the NF-kappaB activation and the protective effect of late preconditioning against myocardial infarction. In contrast, NF-kB activation and late PC effect were completely abrogated by 130 mg/kg of ASA. Our results suggest that nonselective doses of NSAIDs should be used with caution in patients with atherosclerotic cardiovascular disease because they may deprive the heart of its innate defensive response.