A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function in a rapid-pacing-induced model of canine heart failure

Abstract

Objectives: 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.

Methods and results: 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.

Conclusions: 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.

Keywords: 16; 22; 39; 39.2; DCM; Dd; Ds; E; EDWT; EF; ELISA; ESWT; E′; HGF; LV; ONO1301SR; PCR; PLGA; SDF-1; VEGF; dilated cardiomyopathy; early diastolic velocity of the mitral annulus; early transmitral filling wave; ejection fraction; end-diastolic left ventricular dimension; end-diastolic wall thickness; end-systolic left ventricular dimension; end-systolic wall thickness; enzyme-linked immunosorbent assay; hepatocyte growth factor; left ventricular (ventricle); mRNA; messenger RNA; polylactic and glycolic acid polymer; polymerase chain reaction; slow releasing form of ONO1301; stromal-derived factor-1; vascular endothelial growth factor.