title: Endothelial RAGE exacerbates acute postischaemic cardiac inflammation.
abstract: 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.
authors.forename: Tilman
authors.initials: T
authors.lastname: Ziegler
authors.forename: Melanie
authors.initials: M
authors.lastname: Horstkotte
authors.forename: Philipp
authors.initials: P
authors.lastname: Lange
authors.forename: Judy
authors.initials: J
authors.lastname: Ng
authors.forename: Dario
authors.initials: D
authors.lastname: Bongiovanni
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Laugwitz
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Jan
authors.initials: J
authors.lastname: Horstkotte
authors.affiliation: Christian Kupatt, 1. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, TUM Munich, Ismaninger Strasse 22, 81675 Munich, Germany, Tel.: +49 89 4140 9086, E-mail: christian.kupatt@tum.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D009205:Myocarditis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera
chemical_list: C000593873:Ager protein, mouse; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D000067759:Receptor for Advanced Glycation End Products; D018799:Intercellular Adhesion Molecule-1
keywords: PMN; Reperfusion injury; postischaemic inflammation