Myocardial protection by remote preconditioning:: the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase

Objective: Adaptation to ischemia by brief episodes of ischemia and reperfusion (preconditioning) of the heart protects the heart against sustained ischemia, where the transcription factor nuclear factor kappa-B (NFKB) appears crucial for the protection. Preconditioning of the heart may even be evoked by brief episodes of ischemia and reperfusion in other organs. The present study investigates a possible role for NFKB and inducible nitric oxide synthase (iNOS) in adaption to ischemia by remote, delayed protection. Methods: Mice (wild-types, or with targeted deletions of the NFKB p 105 or the iNOS gene) were subjected to cycles of occlusion and reperfusion of both hind limbs, and 24 h later their hearts were isolated and Langendorff-perfused with induced global ischemia and reperfusion. Infarct size was measured. Skeletal muscles from ischemized limbs as well as hearts were also collected for polymerase chain reaction (PCR) and electromobility shift assay (EMSA). Results: Hind limb preconditioning protected left ventricular function and reduced infarct size during reperfusion in wild-type mice. Nuclear translocation of NFKB was detected in both heart and preconditioned skeletal muscle 1-2 h after the preconditioning episodes (EMSA); while cardiac mRNA for iNOS gradually increased in a 24-h time course after hind limb preconditioning (real-time PCR). When hind limbs of mice with targeted deletions for the p 105 subunit of NFKB or the iNOS gene were preconditioned, no beneficial effect was observed in the heart. Conclusions: Delayed cardioprotection induced by hind limb preconditioning involves signaling through NFKB and iNOS. (C) 2004 Elsevier B.V. All rights reserved.