ono-1301 and Fibrosis

The cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy.. Twenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control.. At 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05).. The combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure.

Topics: Animals; Anterior Wall Myocardial Infarction; Biomarkers; Cardiomyopathies; Cardiovascular Agents; Chemistry, Pharmaceutical; Combined Modality Therapy; Coronary Circulation; Delayed-Action Preparations; Disease Models, Animal; Dogs; Fibrosis; Heart Ventricles; Heart-Assist Devices; Natriuretic Peptide, Brain; Peptide Fragments; Prostaglandins I; Prosthesis Design; Pyridines; Recovery of Function; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Chronic injury and inflammation in the liver are associated with the development of liver fibrosis. Expressions of transforming growth factor-β1 (TGF-β1) and hepatocyte growth factor (HGF) participate in the development and suppression, respectively, of liver fibrosis. Here, we investigated the effect of ONO-1301, a synthetic prostaglandin I2/IP receptor agonist, on liver fibrosis and on changes in the hepatic expressions of genes that regulate the progression of fibrosis in mice. Liver fibrosis was caused by the repetitive administration of CCl4 for 12 weeks, with ONO-1301 being administered during the last 4 weeks. The expressions of fibrogenic genes: TGF-β1, connective tissue growth factor, α-smooth muscle actin, type-I collagen, and type-III collagen were upregulated by chronic liver injury, which was associated with the expansion of myofibroblasts and the development of liver fibrosis. Treatment with ONO-1301 increased hepatic HGF mRNA expression, but decreased the expressions of TGF-β1, connective tissue growth factor, α-smooth muscle actin, and type-I and type-III collagen, which was associated with the suppression of myofibroblast expansion and liver fibrosis. Neutralizing antibody for HGF significantly attenuated the suppressive action of ONO-1301 on liver fibrosis and fibrogenic gene expressions. The therapeutic action of ONO-1301 on liver fibrosis may have occurred partly through HGF-mediated pathways.

Topics: Actins; Animals; Disease Models, Animal; Female; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Hepatocyte Growth Factor; Liver Cirrhosis; Mice; Myofibroblasts; Pyridines

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.. 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.. 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.. 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.

Topics: Animals; Animals, Genetically Modified; Cardiomyopathy, Dilated; Cells, Cultured; Chemokine CXCL12; Collagen; Coronary Vessels; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fibroblasts; Fibrosis; Granulocyte Colony-Stimulating Factor; Heart Ventricles; Hepatocyte Growth Factor; Humans; Muscle, Smooth, Vascular; Myocardium; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Pyridines; Regeneration; Sarcoglycans; Time Factors; Vascular Endothelial Growth Factor A; Ventricular Remodeling

ONO-1301, a synthetic prostacyclin agonist with thromboxane synthase inhibitory activity, promotes the production of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) by various cell types. Here, we evaluated the therapeutic efficacy of ONO-1301 in rats with ischemia/reperfusion injury. Ligation of the left anterior descending arteries was performed in 10-week-old Wistar rats, and released 30 min later. A slow-release form of ONO-1301 was administered subcutaneously at 3h and 3 weeks after reperfusion injury. Hemodynamic parameters were significantly improved in the ONO-1301 group. Histological analysis revealed that ONO-1301 suppressed ischemic and fibrotic changes in the myocardium (ischemic area, control group: 58.6 ± 8.7% vs. ONO-1301 group: 44.4 ± 5.8%, fibrotic area, 33.5 ± 5.9% vs. 22.3 ± 6.2%, P<0.05, respectively), and enhanced neovascularization in the border zone. HGF expression was up-regulated by ONO-1301. Double-immunostaining revealed that myofibroblasts in the border zone of ischemic myocardium mainly expressed HGF. Our findings suggest that ONO-1301 might have therapeutic potential in treating ischemic heart disease.

Topics: Animals; Delayed-Action Preparations; Enzyme Inhibitors; Epoprostenol; Fibrosis; Heart; Hepatocyte Growth Factor; Male; Myocardium; Neovascularization, Physiologic; Pyridines; Rats; Rats, Wistar; Reperfusion Injury; Thromboxane-A Synthase

Tubulointerstitial injuries are crucial histological alterations that predict the deterioration of renal function in chronic kidney disease. ONO-1301, a novel sustained-release prostacyclin analog, accompanied by thromboxane synthase activity, exerts therapeutic effects on experimental pulmonary hypertension, lung fibrosis, cardiomyopathy, and myocardial ischemia, partly associated with the induction of hepatocyte growth factor (HGF). In the present study, we examined the therapeutic efficacies of ONO-1301 on tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO). After inducing unilateral ureteral obstruction in C57/BL6J mice, a single injection of sustained-release ONO-1301 polymerized with poly (D,L-lactic-co-glycolic acid) sustained-release ONO-1301 (SR-ONO) significantly suppressed interstitial fibrosis, accumulation of types I and III collagen, increase in the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) cells, and interstitial infiltration of monocytes/macrophages (F4/80(+)) in the obstructed kidneys (OBK; day 7). Treatment with SR-ONO significantly suppressed the increase of the renal levels of profibrotic factor TGF-β and phosphorylation of Smad2/3, and elevated the renal levels of HGF in the OBK. In cultured mouse proximal tubular epithelial cells (mProx24), ONO-1301 significantly ameliorated the expression of fibroblast-specific protein-1 and α-smooth muscle actin as well as phosphorylation of Smad3 and increased the expression of zonula occludens-1 and E-cadherin in the presence of TGF-β1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI(2) receptor-mediated signaling. Administration of rabbit anti-HGF antibodies, but not the control IgG, partly reversed the suppressive effects of SR-ONO on tubulointerstitial injuries in the OBK. Taken together, our findings suggest the potential therapeutic efficacies of ONO-1301 in suppressing tubulointerstitial alterations partly mediated via inducing HGF, an antifibrotic factor counteracting TGF-β.

Topics: Animals; Collagen; Disease Models, Animal; Fibrosis; Kidney; Kidney Diseases; Mice; Phosphorylation; Pyridines; Smad2 Protein; Transforming Growth Factor beta1; Ureteral Obstruction

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood flow and increased collagen synthesis. Administration of growth factors was reported to attenuate left ventricular (LV) remodeling and dysfunction in animal models of dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor and vascular endothelial growth factor from various cell types and ameliorate ischemia-induced LV dysfunction in mice and pigs. We evaluated therapeutic efficacy of ONO-1301 in the Syrian hamster (TO-2), a model of genetically determined dilated cardiomyopathy. Either vehicle or a slow releasing form of ONO-1301 (ONO-1301-PLGA, 10mg/kg/3 weeks) was administered subcutaneously every 3 weeks to TO-2 hamsters from 24 to 32 weeks of age (n=12 for each group). Age-matched F1B hamsters were used as a control. Plasma concentration of HGF was elevated in ONO-1301-PLGA group (p<0.05). Echocardiographic study demonstrated that LV fractional shortening was significantly improved in the ONO-1301-PLGA group (25+/-4%, p<0.01) compared with that in the vehicle group (19+/-2%). Cardiac fibrosis was significantly reduced by ONO-1301-PLGA (p<0.05) as determined by Azan-Mallory staining. Capillary density of left ventricle was markedly reduced in TO-2 hamsters. ONO-1301-PLGA significantly increased capillary density in TO-2 group (p<0.05). ONO-1301 improved LV dysfunction and reduced cardiac fibrosis in the hamster model of dilated cardiomyopathy. ONO-1301 might hold a therapeutic potential in the treatment of dilated cardiomyopathy.

Topics: Animals; Cardiomyopathy, Dilated; Cricetinae; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Enzyme Inhibitors; Fibrosis; Lactic Acid; Male; Myocardium; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Thromboxane-A Synthase; Ventricular Dysfunction, Left