Hyperoxia elicits myocardial protection through a nuclear factor kappaB-dependent mechanism in the rat heart.
OBJECTIVE
Hyperoxia has been previously shown to protect the heart from ischemia-reperfusion injury. In the present study we investigated whether the cardioprotective effects of hyperoxia were dependent on the redox-sensitive transcription factor nuclear factor kappaB.


METHODS
Rats were kept in a hyperoxic (> or =95% O(2)) environment for 60 minutes. Their hearts were isolated immediately afterward, buffer perfused in a Langendorff apparatus, and subjected to 25 minutes of global ischemia and 60 minutes of reperfusion. Cardiac pressures and coronary flow were measured, and infarct size was determined by means of triphenyl tetrazolium chloride staining. Activation of nuclear factor kappaB was assessed by means of the electrophoretic mobility shift assay, whereas the inhibitor IkappaBalpha was evaluated by means of immunoblotting. Pharmacologic inhibition of nuclear factor kappaB was achieved with 2 different agents, SN50 and pyrrolidine dithiocarbamate.


RESULTS
Preischemic exposure to hyperoxia improved postischemic recovery of myocardial contractile function and coronary flow and reduced infarct size. Hyperoxia activated pulmonary and myocardial nuclear factor kappaB. Pretreatment with SN50 (400 microg/kg administered intraperitoneally) or pyrrolidine dithiocarbamate (100 mg/kg administered intraperitoneally) before hyperoxia abolished the functional and infarct-limiting protection. Hyperoxia reduced nuclear factor kappaB activation in the heart during sustained ischemia and reperfusion and increased the cytoplasmatic inhibitory factor IkappaBalpha. Administration of pyrrolidine dithiocarbamate or SN50 during ischemia and reperfusion to isolated hearts from normoxic control animals improved postischemic contractile function and coronary flow and reduced infarct size.


CONCLUSIONS
Hyperoxia protects the rat heart against ischemia-reperfusion injury. The cardioprotection depends on myocardial activation of the transcription factor nuclear factor kappaB. Our results support evidence for a dual role of nuclear factor kappaB in the heart.
Tähepõld
Peeter
P
Crafoord Laboratory of Experimental Surgery, Karolinska Hospital, Stockholm, Sweden.
Vaage
Jarle
J
Starkopf
Joel
J
Valen
Guro
G
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003326:Coronary Circulation; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D018496:Hyperoxia / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000032:analysis; D015151:Immunoblotting; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D010084:Oxidation-Reduction; D010102:Oxygen Inhalation Therapy / Q000379:methods*; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D015533:Transcriptional Activation; D017725:Ventricular Pressure
D000975:Antioxidants; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D010455:Peptides; D011759:Pyrrolidines; C118258:SN50 peptide; D013859:Thiocarbamates; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid