title: Molecular mechanisms mediating preconditioning following chronic ischemia differ from those in classical second window.
abstract: A major difference between experimental ischemic preconditioning (IPC), induced by brief ischemic episodes, and the clinical situation is that patients generally have repetitive episodes of ischemia. We used a swine model to examine differences in genes regulated by classical second-window IPC (SWOP) [two 10-min episodes of coronary artery occlusion (CAO) followed by 24 h reperfusion] compared with repetitive CAO/reperfusion (RCO), i.e., two 10-min CAO 12 h apart, and to repetitive coronary stenosis (RCS), six episodes of 90 min coronary stenosis 12 h apart (n = 5/group). All three models reduced infarct size by 60-85%, which was mediated by nitric oxide in SWOP but not in the other two models. We employed microarray analyses to discover additional molecular pathways intrinsic to models of repetitive ischemia and different from classical SWOP. There was an 85% homology in gene response between the RCO and RCS models, whereas SWOP was qualitatively different. Both RCO and RCS, but not SWOP, showed downregulation of genes encoding proteins involved in oxidative metabolism and upregulation of genes involved in protein synthesis, unfolded protein response, autophagy, heat shock response, protein secretion, and an activation of the NF-kappaB signaling pathway. Therefore, the regulated genes mediating IPC with repetitive ischemia differ radically from SWOP both quantitatively and qualitatively, showing that a repetitive pattern of ischemia, rather than the difference between no-flow vs. low-flow ischemia, dictates the genomic response of the heart. These findings illustrate new cardioprotective mechanisms developed by repetitive IPC, which are potentially more relevant to patients with chronic ischemic heart disease, who are subjected to repetitive episodes of ischemia.
authors.affiliation: Dept. of Cell Biology and Molecular Medicine, Univ. of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Ave., MSB G-609, Newark, NJ 07103, USA. deprech@umdnj.edu
authors.forename: Christophe
authors.initials: C
authors.lastname: Depre
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.forename: You-Tang
authors.initials: YT
authors.lastname: Shen
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019157:Ischemic Preconditioning, Myocardial; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine