Hyperoxia elicits myocardial protection through a nuclear factor κB-dependent mechanism in the rat heart

Abstract 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 κB. Methods: Rats were kept in a hyperoxic (≥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 κB was assessed by means of the electrophoretic mobility shift assay, whereas the inhibitor IκBα was evaluated by means of immunoblotting. Pharmacologic inhibition of nuclear factor κB 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 κB. Pretreatment with SN50 (400 μg/kg administered intraperitoneally) or pyrrolidine dithiocarbamate (100 mg/kg administered intraperitoneally) before hyperoxia abolished the functional and infarct-limiting protection. Hyperoxia reduced nuclear factor κB activation in the heart during sustained ischemia and reperfusion and increased the cytoplasmatic inhibitory factor IκBα. 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 κB. Our results support evidence for a dual role of nuclear factor κB in the heart. J Thorac Cardiovasc Surg 2003;125:650-60