Non‐viral delivery of therapeutic nucleic acids to investigate the role of transcriptional networks in the ischemic heart

Abstract

Nuclear factor‐kappaB (NF‐κB) is a key player in the physiological outcomes of myocardial ischemic events including ischemia‐reperfusion (I/R), permanent occlusion (PO), and the cardioprotection of ischemic preconditioning (IPC). Our lab has demonstrated that NF‐κB plays a protective role in late IPC and after PO, yet has an injurious role after I/R. Such results suggest the transcriptional activation of differential gene sets by each ischemic event. This was confirmed in our lab by a gene microarray analysis comparing I/R, PO, and IPC. Our microarray results also suggested potential cross‐talk of NF‐κB with other transcriptional networks, such as those regulated by HIF‐1α, AP‐1, and HSF‐1. Our aim is to deliver transcription factor decoys and interfering RNAs to the heart in vivo and begin to elucidate the relative role of these gene networks in myocardial ischemia. We have demonstrated nucleic acid delivery to the heart via novel polyglycoamidoamine (PGAA) glycopolymers that act through formation of nanoscale “polyplexes” and enhance cellular uptake via endocytosis resulting in nearly transmural transfection of the myocardium without eliciting cytotoxicity. Our work provides a high‐throughput in vivo approach to the study of the regulation of interlaced gene networks during myocardial ischemic events and will augment the identification of new clinical targets for the treatment of myocardial ischemia. This work was supported by NIH grant R01 HL63034 (WKJ) and NSF award number 0333377.