Synthetic prostacyclin agonist, ONO1301, enhances endogenous myocardial repair in a hamster model of dilated cardiomyopathy: a promising regenerative therapy for the failing heart.
OBJECTIVE
Remodeling of the left ventricle (LV) in idiopathic dilated cardiomyopathy (IDCM) is known to be associated with multiple pathologic changes that endogenous factors, such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), protect against. Although a clinically relevant delivery method of these factors has not been established, ONO1301, a synthetic prostacyclin agonist, has been shown to upregulate multiple cardioprotective factors, including HGF and VEGF, in vivo. We thus hypothesized that ONO1301 may reverse LV remodeling in the DCM heart.


METHODS
ONO1301 dose-dependently added to the normal human dermal fibroblasts and human coronary artery smooth muscle cells in vitro, to measure the expression of HGF, VEGF, stromal cell-derived factor (SDF)-1, and granulocyte-colony stimulating factor (G-CSF), assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. δ-Sarcoglycan-deficient J2N-k hamsters, which is an established DCM model, were treated by epicardial implantation of an atelocollagen sheet with or without ONO1301 immersion or sham operation.


RESULTS
ONO1301 dose-dependently upregulated expression of these 4 factors in vitro. ONO1301 treatment, which induced dominant elevation of ONO1301 levels for 2 weeks, significantly preserved cardiac performance and prolonged survival compared with the other groups. This treatment significantly upregulated expressions of cardioprotective factors and was associated with increased capillaries, attenuated fibrosis, and upregulation of α-sarcoglycan in the DCM heart.


CONCLUSIONS
ONO1301 atelocollagen-sheet implantation reorganized cytoskeletal proteins, such as α-sarcoglycan, increased capillaries, reduced fibrosis, and was associated with upregulated expression of multiple cardioprotective factors, leading to preservation of cardiac performance and prolongation of survival in the δ-sarcoglycan-deficient DCM hamster.
Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Kazuhiko
K
Ishimaru
Shigeru
S
Miyagawa
Satsuki
S
Fukushima
Atsuhiro
A
Saito
Yoshiki
Y
Sakai
Takayoshi
T
Ueno
Yoshiki
Y
Sawa
D000818:Animals; D030801:Animals, Genetically Modified; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D003094:Collagen; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects*; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D004337:Drug Carriers; C066855:HGF protein, human; D011725:Pyridines; D049031:Sarcoglycans; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059821:atelocollagen; D016179:Granulocyte Colony-Stimulating Factor; C105488:ONO 1301; D017228:Hepatocyte Growth Factor; D003094:Collagen
16; 17.1; CoASMC; DCM; Dd/Ds; EF; ELISA; G-CSF; GAPDH; HCoASMC; HGF; IDCM; IPR; LV; N group; NHDF; O group; PCR; PLGA; S group; SDF-1; VEGF; atelocollagen sheet containing ONO1301; atelocollagen sheet without ONO1301; coronary artery smooth muscle cell; diastolic/systolic dimensions; dilated cardiomyopathy; ejection fraction; enzyme-linked immunosorbent assay; glyceraldehyde-3-phosphate dehydrogenase; granulocyte colony stimulating factor; hepatic growth factor; human coronary artery smooth muscle cell; idiopathic dilated cardiomyopathy; left ventricular (ventricle); normal human dermal fibroblast; polylactic-co-glycolic acid copolymer; polymerase chain reaction; prostacyclin receptor; sham group; stromal cell–derived factor-1; vWF; vascular endothelial growth factor; von Willebrand factor