NFkappaB and AP-1 differentially contribute to the induction of Mn-SOD and eNOS during the development of oxidant tolerance.
Exposure of cardiac myocytes to anoxia/reoxygenation (A/R) increases myocyte oxidant stress and converts the myocytes to a proinflammatory phenotype. These oxidant-induced effects are prevented by pretreatment of the myocytes with an oxidant stress (A/R or H2O2) 24 h earlier (oxidant tolerance). Although NF-kappaB and AP-1 (nuclear signaling) and Mn-SOD and eNOS (effector enzymes) have been implicated in the development oxidant tolerance, the precise relationship between the nuclear transcription factors and the effector enzymes in the development of oxidant tolerance has not been defined. Herein, we show that an initial A/R challenge results in nuclear accumulation of both NF-kappaB and AP-1 (EMSA). In addition, blockade of nuclear translocation of NF-kappaB (SN50) or AP-1 (decoy oligonucleotide) prevents the development of oxidant tolerance, i.e., the second A/R challenge produces the same quantitative effects as the initial A/R challenge. In this model, nuclear translocation of both NF-kappaB and AP-1 is required for induction of Mn-SOD, while nuclear translocation of AP-1, but not NF-kappaB, is a prerequisite for induction of eNOS. Collectively, our findings indicate that NF-kappaB and AP-1 work in concert to ensure the induction eNOS and Mn-SOD, which in turn are important for the development of oxidant tolerance.
Rui
Tao
T
Vascular Cell Biology Laboratory, Centre for Critical Illness Research, Lawson Health Research Institute and Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada .
Kvietys
Peter R
PR
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015233:Models, Statistical; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D021381:Protein Transport; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016328:NF-kappa B; D016877:Oxidants; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase