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1 Cardiology Division, Virginia Commonwealth University, Richmond, VA, USA
2 Pulmonary Disease and Critical Care Medicine Division - Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
* To whom correspondence should be addressed. E-mail: aafowler{at}vcu.edu.
The CXC chemokine interleukin-8 (IL-8) which promotes adhesion, activation and transmigration of polymporphonuclear neutrophils (PMN) has been associated with production of tissue injury in reperfused myocardium. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric peptide that is a key regulator of genes such as heme oxygenase-1 (HO-1) expressed under hypoxic conditions. We hypothesized that HO-1 plays an important role in regulating proinflammatory mediator production under conditions of ischemia/reperfusion. HIF-1 was activated in HMEC-1 using the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). DMOG significantly attenuated cytokine-induced IL-8 promoter activity and protein secretion and cytokine-induced neutrophil migration across HMEC-1 monolayers. In vivo studies in a rabbit model of myocardial ischemia/reperfusion showed that rabbits pretreated with a 20 mg/kg DMOG infusion (n=6) 24 hours prior to study exhibited a 21.58±1.76% infarct size as compared to 35.25±2.06% in saline-treated ischemia/reperfusion animals (n=6, 
reduction = 39%, p<0.001). In DMOG pretreated (20 mg/kg) animals plasma IL-8 levels at 3 hours following onset of reperfusion were 790±40 pg/ml vs. 405±40 pg/ml in saline-treated ischemia/reperfusion animals (p<0.001). DMOG pretreatment reduced myocardial myeloperoxidase, activity expressed as PMN per gram of myocardium to 1.43±0.59 vs. 4.86±1.1 (p=0.012) in saline-treated ischemia/reperfused hearts. Both in vitro and in vivo DMOG attenuated IL-8 production was associated with robust HO-1 expression. Thus our data shows that HIF-1 activation induces substantial HO-1 expression which is associated with attenuated pro-inflammatory chemokine production by microvascular endothelium in vitro and in vivo.
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