Local delivery of synthetic prostacycline agonist augments collateral growth and improves cardiac function in a swine chronic cardiac ischemia model

Abstract

Aims 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. Main methods 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. Key findings 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). Significance 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.