Myocardial protection by hyperoxia

Abstract: Oxygen is essential for normal respiration in aerobic organisms, and prolonged deficit of oxygen always has detrimental consequences.However, all aerobic life forms are faced with the threat of oxidation from molecular oxygen. Reactive oxygen intermediates have been suggested to have an essential role in the pathogenesis of ischaemia-reperfusion injury. At high fractions and prolonged exposure, hyperoxia may lead to excessive generation of reactive oxygen intermediates overwhelming the cellular antioxidant defense and inducing oxidative damage. Contrary to these detrimental effects, reactive oxygen intermediates have recently been suggested play a physiological role acting as signal transduction. Theoretically, increased oxygen fractions in inspired air may have beneficial effects. In the present study, we demonstrate that in vivo exposure of rats or mice to increased oxygen fraction induced ex vivo functional protection of the heart, and reduced the extent of myocardial necrosis after induced global or regional ischaemia. The obtained cardioprotection was evident when the heart was isolated and perfused immediately afterwards, or when it was perfused 24 hours later. The protection depended on the inspired oxygen fraction and the duration of hyperoxic exposure. The vasomotor response of isolated aortic rings was also modified by hyperoxia. Hyperoxia elicited a systemic low-graded oxidative stress, and caused pulmonary and myocardial nuclear translocation of the transcription factor nuclear factor kappa-B (NF-kappa-B) Hyperoxia reduced activation of NF-kappa-B during sustained ischaemia and reperfusion, and increased the NF-kappa-B cytoplasmatic inhibitory protein I-kappa-B-alpha. Administration of NF-kappa-B inhibitors during ischaemia and reperfusion improved contractile function and reduced infarct size in hearts from normoxic control animals. These findings demonstrate that hyperoxia elicits myocardial protection through a NF-kappa-B-dependent mechanism, and support evidence for a dual role of NF-kappa-B in the heart. In summary, a novel concept of vascular and myocardial protection through exposure of animals to increased oxygen fraction was established in the present work. Hyperoxia may be directly employed in patients for increased endogenous cell defence