title: Preconditioning potentiates redox signaling and converts death signal into survival signal.
abstract: Reactive oxygen species (ROS) play a crucial role in the pathophysiology of ischemic heart disease by causing cardiac dysfunction and cell death. Several redox-sensitive anti- and pro-apoptotic transcription factors including NFkappaB and AP-1 progressively and steadily increase in the heart as a function of the duration of ischemia and reperfusion. When the heart is preconditioned to ischemic stress by repeated short-term ischemia and reperfusion, NFkappaB remains high while AP-1 is lowered to almost baseline value. The anti-apoptotic gene Bcl-2 is downregulated in the ischemic/reperfused heart, while it is upregulated in the adapted myocardium. Cardioprotective abilities of the preconditioning are abolished when heart is pre-perfused with N-acetyl cysteine, a scavenger for ROS, suggesting the role of ROS in redox signaling. Mammalian heart is protected by several defense systems which include among others, redox-regulated protein, thioredoxin. Reperfusion of ischemic myocardium results in the downregulation of thioredoxin 1 (Trx 1) expression, which was upregulated in the preconditioned myocardium. The increased expression of Trx 1 is completely blocked with an inhibitor of Trx 1, CDDP, which also abolished cardioprotection afforded by ischemic adaptation. The cardioprotective role of Trx 1 is confirmed further with transgenic mouse hearts overexpressing Trx 1. The Trx 1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size and apoptosis as compared to the corresponding wild-type mouse hearts. Taken together, preconditioning appears to potentiate redox signaling, which converts the "death signal" into "survival signal."
authors.affiliation: Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA. ddas@neuron.uchc.edu
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors