Abstract 12401: Dendritic Cell Depletion Reduces Ischemic Reperfusion Injury
Dendritic cells (DCs), which bridge the innate and adaptive immune response, are an important component in the pathogenesis of hepatic and renal ischemic/reperfusion (I/R) injury, however, the effect of DCs in myocardial I/R injury is unknown. Our previous study revealed a crucial role for tumor necrosis factor alpha (TNF) in mediating I/R injury because mice with cardiac-specific over-expression of TNF demonstrated augmented endothelial injury. Accordingly, we hypothesized that DCs play a pivotal role in regulating the expression of TNF during I/R injury. To test this hypothesis, we employed a mouse model of myocardial I/R (30 minutes/24 hours) in wild type (WT) and DC deficient (CD11c) mice. A sham group was subjected to the same surgical interventions without performing occlusions of the left anterior descending coronary artery for both WT and CD11c mice. DC deficient mice were obtained by intra-peritoneal injection of diphtheria toxin (DT) to mice with transgenic DT receptors (DTR). The measurements of myocardial infarct size using Triphenyltetrazolium chloride (TTC) staining showed that myocardial infarct size was smaller in CD11c-DTR compared with WT following myocardial I/R injury (p<0.01). Then, cardiac function was also measured by performing closed-chest hemodynamic assay using a Millar micro-catheter/sensor. We found that cardiac function was impaired in WT I/R vs. WT sham mice, but CD11c-DTR I/R mice shows a significantly increased ejection fraction and reduction of end-systolic and end-diastolic volume, respectively. This indicates that depletion of DCs limited the development of dilated cardiomyopathy following myocardial I/R injury. Our western blotting results showed that myocardial TNF protein expression was higher in WT I/R vs. WT sham mice (p<0.01). Most importantly, protein expression of TNF was attenuated in CD11c-DTR I/R mice compared with WT I/R and CD11c-DTR sham mice (p<0.01). The proposed mechanism whereby I/R induces cardiomyopathy is through DC activation, that then stimulates expression/production of TNF, which leads to increased infarct size and impaired cardiac function, suggesting the potential for new treatment approaches to promote cardiovascular health in ischemic heart disease.
- © 2010 by American Heart Association, Inc.