title: Identification of a NF-κB cardioprotective gene program: NF-κB regulation of Hsp70.1 contributes to cardioprotection after permanent coronary occlusion.
abstract: The transcription factor Nuclear Factor Kappa B (NF-κB) has been shown to be cardioprotective after permanent coronary occlusion (PO) and late ischemic preconditioning (IPC), and yet it is cell injurious after ischemia/reperfusion (I/R) in the heart. There is limited information regarding NF-κB-dependent cardioprotection, and the NF-κB-dependent genes that contribute to the cardioprotection after PO are completely unknown. The objective of the study was to identify NF-κB-dependent genes that contribute to cardioprotection after PO. Microarray analysis was used to delineate genes that potentially contribute to the NF-κB-dependent cardioprotection by determining the overlap between the set of PO regulated genes and genes regulated by NF-κB, using mice with genetic abrogation of NF-κB activation in the heart. This analysis identified 16 genes as candidates for NF-κB-dependent effects after PO. This set of genes overlaps with, but is significantly different from the set of genes we previously identified as regulated by NF-κB after IPC. The genes encoding heat shock protein 70.3 (hspa1a) and heat shock protein 70.1 (hspa1b) were the most significantly regulated genes after PO and were up-regulated by NF-κB. Results using knockout mice show that Hsp70.1 contributes to NF-κB-dependent cardioprotection after PO and likely underlies, at least in part, the NF-κΒ-dependent cardioprotective effect. Our previous results show that Hsp70.1 is injurious after I/R injury. This demonstrates that, like NF-κB itself, Hsp70.1 has antithetical effects on myocardial survival and suggests that this may underlie the similar antithetical effects of NF-κB after different ischemic stimuli. The significance of the research is that understanding the gene network regulated by NF-κB after ischemic insult may lead to identification of therapeutic targets more appropriate for clinical development.
authors: Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
authors: Michael E
authors: ME
authors: Wilhide
authors: Michael
authors: M
authors: Tranter
authors: Xiaoping
authors: X
authors: Ren
authors: Jing
authors: J
authors: Chen
authors: Maureen A
authors: MA
authors: Sartor
authors: Mario
authors: M
authors: Medvedovic
authors: W Keith
authors: WK
authors: Jones
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D054059:Coronary Occlusion / Q000378:metabolism*; D053263:Gene Regulatory Networks; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015533:Transcriptional Activation
chemical_list: D002316:Cardiotonic Agents; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; C081884:heat-shock protein 70.1