Postinfarct active cardiac-targeted delivery of erythropoietin by liposomes with sialyl Lewis X repairs infarcted myocardium in rabbits

• Published in: American journal of physiology. Heart and circulatory physiology 2013-04, Vol.304 (8), p.H1124-H1133
• Main Authors: Yamada, Yoshihisa, Kobayashi, Hiroyuki, Iwasa, Masamitsu, Sumi, Shohei, Ushikoshi, Hiroaki, Aoyama, Takuma, Nishigaki, Kazuhiko, Takemura, Genzou, Fujiwara, Takako, Fujiwara, Hisayoshi, Kiso, Makoto, Minatoguchi, Shinya
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Drug Delivery Systems; eIF-2 Kinase - drug effects; eIF-2 Kinase - metabolism; Erythropoietin - administration & dosage; Glycoproteins; Heart attacks; Hematinics - administration & dosage; Liposomes; Male; Matrix Metalloproteinase 1 - drug effects; Matrix Metalloproteinase 1 - metabolism; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Oligosaccharides - administration & dosage; Phosphorylation - drug effects; Physiology; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rabbits; Signal transduction; STAT3 Transcription Factor - drug effects; STAT3 Transcription Factor - metabolism; Vascular Endothelial Growth Factor A - drug effects; Vascular Endothelial Growth Factor A - metabolism; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00707.2012

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.