Endothelial RAGE exacerbates acute postischaemic cardiac inflammation

Summary

Advanced glycation end-products (AGEs) interact with their receptor RAGE, leading to an inflammatory state. We investigated the role of RAGE in postischaemic leukocyte adhesion after myocardial infarction and its effect on postischaemic myocardial function. Wildtype (WT), ICAM-1^-/-, RAGE^-/- or ICAM-1/RAGE^-/- mice underwent 20 minutes (min) of LAD-occlusion followed by 15 min of reperfusion. We applied in vivo fluorescence microscopy visualising Rhodamine-6G labelled leukocytes. To differentiate between endothelial and leukocyte RAGE, we generated bone marrow chimeric mice. Invasive hemodynamic measurements were performed in mice undergoing 45 min of myocardial ischaemia (via LAD-occlusion) followed by 24 hours of reperfusion. Left-ventricular developed pressure (LVDP) was assessed by insertion of a millar-tip catheter into the left ventricle. In the acute model of myocardial ischaemia, leukocyte retention (WT 68 ± 4 cells/ hpf) was significantly reduced in ICAM-1^-/- (40 ± 3 cells/hpf) and RAGE^-/- mice (38 ± 4 cells/hpf). ICAM-1/RAGE^-/- mice displayed an additive reduction of leukocyte retention (ICAM-1/RAGE^-/- 15 ± 3 cells/ hpf). Ly-6G+ neutrophil were predominantly reduced in ICAM-1/RAGE^-/- hearts (28%), whereas Ly-6C+ proinflammatory monocytes decreased to a lesser extent (55%). Interestingly, PMN recruitment was not affected in chimeric mice with RAGE deficiency in BM cells (WT mice reconstituted with ICAM-1/RAGE^-/- BM: 55 ± 4 cells/hpf) while in mice with global RAGE deficiency (ICAM-1/RAGE^-/- mice reconstituted with ICAM-1/RAGE^-/- BM) leucocyte retention was significantly reduced (13 ± 1 cells/hpf), similar to non-transplanted ICAM/ RAGE^-/- mice. Furthermore, postischaemic LVDP increased in ICAM-1/RAGE^-/- animals (98 ± 4 mmHg vs 86 ± 4 mmHg in WT mice). In conclusion, combined deficiency of ICAM-1 and RAGE reduces leukocyte influx into infarcted myocardium and improves LV function during the acute phase after myocardial ischaemia and reperfusion. RAGE represents an additional pro-inflammatory endothelial mediator of ischaemia-reperfusion injury.

Keywords

Reperfusion injury - PMN - postischaemic inflammation

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