title: Postinfarct active cardiac-targeted delivery of erythropoietin by liposomes with sialyl Lewis X repairs infarcted myocardium in rabbits.
abstract: We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl Lewis(X) (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.
authors: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Yoshihisa
authors: Y
authors: Yamada
authors: Hiroyuki
authors: H
authors: Kobayashi
authors: Masamitsu
authors: M
authors: Iwasa
authors: Shohei
authors: S
authors: Sumi
authors: Hiroaki
authors: H
authors: Ushikoshi
authors: Takuma
authors: T
authors: Aoyama
authors: Kazuhiko
authors: K
authors: Nishigaki
authors: Genzou
authors: G
authors: Takemura
authors: Takako
authors: T
authors: Fujiwara
authors: Hisayoshi
authors: H
authors: Fujiwara
authors: Makoto
authors: M
authors: Kiso
authors: Shinya
authors: S
authors: Minatoguchi
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000008:administration & dosage*; D006397:Hematinics / Q000008:administration & dosage*; D008081:Liposomes; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009844:Oligosaccharides / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D019892:eIF-2 Kinase / Q000187:drug effects / Q000378:metabolism
chemical_list: D004921:Erythropoietin; D006397:Hematinics; D008081:Liposomes; D020781:Matrix Metalloproteinase 1; D009844:Oligosaccharides; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D000080506:Sialyl Lewis X Antigen; D042461:Vascular Endothelial Growth Factor A; D019892:eIF-2 Kinase