Effect of acetylsalicylic acid on nuclear factor-kappaB activation and on late preconditioning against infarction in the myocardium.
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.
Jancso
Gabor
G
Department of Surgical Research and Techniques, University of Pecs, Medical Faculty, Pécs, Hungary. jancsogabor@hotmail.com
Cserepes
Barbara
B
Gasz
Balázs
B
Benko
Laszlo
L
Ferencz
Andrea
A
Borsiczky
Balazs
B
Lantos
Janos
J
Dureja
Anjali
A
Kiss
Katalin
K
Szeberényi
Jozsef
J
Roth
Elizabeth
E
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001241:Aspirin / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D001241:Aspirin