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 (NFkappaB) 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 NFkappaB and inducible nitric oxide synthase (iNOS) in adaption to ischemia by remote, delayed protection.


METHODS
Mice (wild-types, or with targeted deletions of the NFkappaB p105 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 NFkappaB 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 p105 subunit of NFkappaB 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 NFkappaB and iNOS.
Li
Guohu
G
Crafoord Laboratory for Experimental Surgery L6.00, Karolinska Hospital, S-17176 Stockholm, Sweden.
Labruto
Fausto
F
Sirsjö
Allan
A
Chen
Fei
F
Vaage
Jarle
J
Valen
Guro
G
D000818:Animals; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014178:Translocation, Genetic; D016277:Ventricular Function, Left
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse