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-κB-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.

Toll-like Receptor Agonists and Febrile Range Hyperthermia Synergize to Induce Heat Shock Protein 70 Expression and Extracellular Release

“…HSF1 trimerization and activation of its transactivation domain are regulated by multiple serine and threonine phosphorylation events. Transcription of Hsps is also influenced by other transcription factors, including STAT-1, STAT-3, and NF-IL-6 (22)(23)(24), tonicity enhancer-binding protein and hypoxia-inducible factor 1 (25) and NFB (26). We previously showed that HSF1 trimerization and Hsp70 transcription were activated in A549 cells by exposure to mild hyperthermia (38.5°C), that Hsp70 transcription increased as the exposure temperature increased from 38.5°C to 42°C, and that increased transcription was associated with additional HSF1 phosphorylation but not additional HSF1 trimerization (27).…”

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

“…However, this pattern overlooks that fact that NF-B is a vital part of our innate immunity and promotes survival signals (47). Indeed, some evidence suggests that NF-B promotes cardioprotection in models of ischemic preconditioning and coronary ligation (46,49). Central to reconciling many of these issues is enhanced understanding of the role of its principal subunit.…”

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…Importantly, these paths are inhibited by A 2A Rs in other cells, with exogenous agonism decreasing [44,45] and A 2A R KO increasing NFκB activity [6]. Nonetheless, these paths can also promote myocardial stress-resistance and survival under conditions that include inflammatory cytokine challenge [46][47][48]. The molecular underpinnings of endotoxemic myocarditis in vivo warrant further investigation, as do the mechanisms countering this dysfunction (including A 2A R activity).…”

“…Also shown is the ratio reflecting the number of molecules in a given path that meet cut-off criteria for differential expression, divided by the total number of molecules in the path of the distal transcriptional effector IκBζ is predicted to limit effects of up-stream changes. Failure of A 2A R KO to modify changes in genes recently implicated in cardioprotective effects of NFκB signalling [47] (including induction of Ptx3, Plscr1, Sfi1 and Igfbp3 and repression of Car3, Dkk3, ai605517 and Grhl2) suggests receptor activity might selectively modify injurious rather than protective aspects of NFκB signalling.…”