title: Sustained-release delivery of prostacyclin analogue enhances bone marrow-cell recruitment and yields functional benefits for acute myocardial infarction in mice.
abstract: BACKGROUND
  A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice.
  
  
  RESULTS
  ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group.
  
  
  CONCLUSIONS
  Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.
authors.affiliation: Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Satsuki
authors.initials: S
authors.lastname: Fukushima
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ishimaru
authors.forename: Nagako
authors.initials: N
authors.lastname: Sougawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000008:administration & dosage* / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling
chemical_list: D054377:Chemokine CXCL12; D011725:Pyridines; D019718:Receptors, CXCR4; C105488:ONO 1301; D011464:Epoprostenol
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