ono-1301 and Cardiomyopathy--Dilated

Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM.. ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area.. Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.

Topics: Animals; Cardiac Catheterization; Cardiac Pacing, Artificial; Cardiomyopathy, Dilated; Cardiovascular Agents; Cell Line; Chemistry, Pharmaceutical; Cytokines; Delayed-Action Preparations; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Carriers; Echocardiography, Doppler; Fibroblasts; Heart Failure; Humans; Injections, Intramuscular; Lactic Acid; Microscopy, Electron; Mitochondria, Heart; Myocardium; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Recovery of Function; RNA, Messenger; Stroke Volume; Time Factors; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

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

Injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis sometimes progresses to dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor (HGF) from various cell types and ameliorates ischemia-induced left ventricle dysfunction in the mouse, rat and pig. Here, we investigated the therapeutic efficacy of ONO-1301 in a rat model of myosin-induced experimental autoimmune myocarditis, in which the heart transits from an acute inflammatory phase to a chronic dilated cardiomyopathy phase. Four weeks after myosin injection to Lewis rats, ONO-1301 (6 mg/kg/day) was orally administered for 4 weeks (ONO-1301 group). Hemodynamic parameters and plasma brain natriuretic peptide (BNP) level were significantly improved by ONO-1301. Histological analysis revealed that capillary density in the myocardium was significantly increased by ONO-1301. ONO-1301 increased circulating endothelial progenitor cells (EPC) as determined by FACS analysis. These beneficial effects of ONO-1301 were partially abrogated by a neutralizing anti-HGF antibody (8 mg/kg/dose). These findings indicate beneficial effects of ONO-1301 in a rat experimental autoimmune myocarditis model.

Topics: Administration, Oral; Animals; Autoimmune Diseases; Cardiomyopathy, Dilated; Disease Models, Animal; Endothelial Cells; Hemodynamics; Male; Myocarditis; Myosins; Natriuretic Peptide, Brain; Pyridines; Rats; Rats, Inbred Lew; Stem Cells

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