Co‐regulation of Cardioprotective Gene Expression by NF‐kappaB, AP‐1, and STAT3 in Late Phase Ischemic Preconditioning

Abstract

IntroductionWe have shown that NF‐κB regulates the expression of over 200 genes in late ischemic preconditioning (IPC) and its activation is necessary for the cardioprotection of late IPC. We have also demonstrated that Hsp70.3 is one of these NF‐κB regulated genes whose expression is necessary to elicit late IPC protection.ResultsUsing a novel non‐viral DNA delivery agent to apply transcription factor decoys to the in vivo murine heart, we show that, in addition to NF‐κB, transcriptional blockade of AP‐1, or STAT3 prior to IPC abrogates the late phase of cardioprotection. We hypothesize that NF‐κB, AP‐1, and STAT3 co‐regulate a common subset of genes, including Hsp70.3, that are critical for late phase IPC cardioprotection. Results using in vitro reporter assays demonstrate coordinated regulation of the Hsp70.3 promoter by NF‐κB, AP‐1, and STAT‐3. We also used PCR based gene microarrays to examine in vivo expression changes of 238 previously identified NF‐κB‐dependent genes under conditions of AP‐1 and STAT3 inhibition after IPC to identity additional genes co‐regulated by this trio of IPC requisite transcription factors.ConclusionsThe set of genes whose expression is co‐dependent on multiple cardioprotective transcription factors after IPC are likely to underlie common critical pathways of cardioprotection and may represent novel therapeutic targets for the treatment of ischemic heart disease.This work was supported by NIH grant R01 HL63034 (WKJ).