ono-1301 and Myocardial-Ischemia

We hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO-1301SR, a slow-release synthetic prostacyclin agonist-inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart.. A minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO-1301SR only, and ONO-1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting.. In an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a. ONO-1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model.

Topics: Angiogenic Proteins; Animals; Combined Modality Therapy; Coronary Circulation; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Microcirculation; Microvessels; Myocardial Ischemia; Neovascularization, Physiologic; Omentum; Pyridines; Recovery of Function; Signal Transduction; Surgical Flaps; Swine; Swine, Miniature; Time Factors; Ventricular Function, Left

It was reported that administration of angiogenic growth factors can augment collateral growth in ischemic tissues. It is assumed that angiogenic effects of cell transplantation may be mainly mediated by secretion of angiogenic cytokines. We tested feasibility of clinical use of ONO-1301, a synthetic small molecule that stimulates secretion of growth factors from various cell types, to treat patients with chronic myocardial ischemia.. Effects of ONO-1301 on fibroblasts and endothelial cells were evaluated in vitro. We examined the efficacy of local delivery of ONO-1301 in models of rat hindlimb ischemia and swine chronic ischemic myocardium.. ONO-1301 stimulated hepatocyte growth factor secretion from human fibroblasts. ONO-1301 promoted vascular-like tube formation by endothelial cells in vitro. Direct injection of a slow-release form of ONO-1301 (SR-ONO) to rat hindlimb ischemic muscle enhanced perfusion recovery. In a swine cardiac ischemia model, direct injection of SR-ONO into the ischemic myocardium significantly augmented collateral formation (SR-ONO vs. control; 1.7+/-0.2 vs. 1.0+/-0.2 Rentrop score), with improved local ventricular wall motion, reduced enlargement of left ventricular diastolic volume (49.5+/-1.9 mL vs. 59.7+/-4.2 mL) and increased cardiac index (4.2+/-0.1 vs. 3.4+/-0.2 L/min/m(2)). Histological analysis revealed that SR-ONO suppressed fibrosis in ischemic tissue (collagen volume fraction; 7.5+/-1.1% vs. 12.8+/-2.2%) and enhanced neovascularization (capillary density, 275.6 vs. 159.3/mm(2); arterioles 36.6 vs. 25.5 /mm(2)).. Local delivery of SR-ONO might be effective for therapeutic angiogenesis and propose that local administration of slow-release of synthetic small molecules represents new strategy for therapeutic angiogenesis.

Topics: Animals; Cells, Cultured; Collateral Circulation; Delayed-Action Preparations; Disease Models, Animal; Endothelium, Vascular; Fibroblasts; Hepatocyte Growth Factor; Hindlimb; Laser-Doppler Flowmetry; Male; Microcirculation; Myocardial Ischemia; Neovascularization, Pathologic; Prostaglandins I; Pyridines; Rats; Rats, Sprague-Dawley; Swine

It has been shown previously that administration of angiogenic growth factors as genes or proteins can augment collateral growth in ischaemic tissues. In the present study, we have investigated the effect of ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase-inhibitory activity, on expression of endogenous growth factors and angiogenesis. ONO-1301 induced secretion of HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) from cultured normal human dermal fibroblasts in a dose-dependent manner. Dibutyryl cAMP, an analogue of cAMP, and forskolin, an adenylate cyclase activator, mimicked the effect of ONO-1301. Conversely, Rp-cAMP (adenosine 3',5'-cyclic monophosphorothioate), an inhibitor of cAMP, partially inhibited the effect of ONO-1301, suggesting that cAMP mediated the effect of ONO-1301 in up-regulating the expression of HGF and VEGF, at least in part. ONO-1301 promoted tube-like formation by HUVECs (human umbilical vein endothelial cells) when co-cultured with fibroblasts, and the angiogenic effect of ONO-1301 was abrogated by administration of a neutralizing antibody against HGF or VEGF. To generate a slow-releasing form of ONO-1301, ONO-1301 was mixed with poly(DL-lactic-co-glycolic acid). The slow-releasing form of ONO-1301 was injected directly into the ischaemic myocardium of mice immediately after ligation of the left anterior descending artery. The slow-releasing form of ONO-1301 up-regulated HGF and VEGF expression and increased capillary density in the border zone (342.7+/-29.7 capillaries/mm(2) in controls compared with 557.2+/-26.7 capillaries/mm(2) in treated animals; P<0.01) at 7 days. The slow-releasing form of ONO-1301 ameliorated left ventricular enlargement after 28 days and improved survival rate. In conclusion, our results indicate that ONO-1301 up-regulated endogenous growth factors and promoted angiogenesis in response to acute ischaemia. Therefore ONO-1301 might have a therapeutic potential in treating ischaemic diseases.

Topics: Animals; Dilatation, Pathologic; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoprostenol; Fibroblasts; Hepatocyte Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred Strains; Myocardial Ischemia; Myocardium; Neovascularization, Pathologic; Pyridines; Thromboxane-A Synthase; Up-Regulation; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left