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| The Role of Inflammation and NF-κB in Myocardial Ischemia-Reperfusion Injury |
| ¹Department of Internal Medicine, Chonnam National University Hospital, ²Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, South Korea, |
| Youngkeun Ahn¹, Yong-Sook Kim¹,Hyun Kook²,Sang Yup Lim¹,Kyung Ho Yun¹,Dong Goo Kang¹,Sang Hyun Lee¹,Yeon Sang Lee¹,Kye Hun Kim¹,Seo Na Hong¹,Young Joon Hong¹,Hyung Wook Park¹,Ju Han Kim¹,Weon Kim¹,Myung Ho Jeong¹,Jeong Gwan Cho¹,Jong Chun Park¹,Jung Chaee |
NF-κB transcription factors drive expression of many genes involved in inflammation and cell survival, both important in ischemia-reperfusion (IR) injury. IKK-β can mediate NF-κB activation through phosphorylation of IB, however, alternative pathways of activation exist. To test the role of IKK-β in cardiac IR injury, we performed cardiac gene transfer of dominant negative IKK-β (dnIKK-β) in rats 48 hr prior to IR. We found that adenoviral gene transfer resulted in regional transgene expression comprising ~60% of the ischemic area. Ad.dnIKK-β reduced IR-induced NF-κB translocation and IκB degradation, and blocked induction of the NF-κB-dependent inflammatory chemokine, MCP-1, in the ischemic area compared with Ad.EGFP.β-gal treated rats (p<0.05). Neutrophil infiltration in the ischemic area (as indicated by myeloperoxidase activity) was decreased by 33% in the Ad.dnIKK-β treated rats compared with Ad.EGFP.β-gal treated rats (p<0.05). Ad.dnIKK-β also reduced IR-induced apoptosis, reflected in attenuated DNA laddering compared with buffer or Ad.EGFP.β-gal injected rats. The ischemic area was not affected by dnIKK-β expression. However, Ad.dnIKK-β reduced infarction (%MI) by 78% compared with Ad.EGFP.β-gal treated rats (p<0.001). Thus, in vivo gene transfer of dnIKK-β prevents IR-induced activation of NF-κB. In this setting, abrogation of pro-inflammatory signals appears more important than loss of NF-κB dependent survival factors, resulting in an overall reduction in apoptosis and infarct size. These data suggest that IKK-β may represent a valuable target for therapeutic intervention in IR injury.
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