A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function.

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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 Tomonori Shirasaka, MD, Shigeru Miyagawa, MD, PhD, Satsuki Fukushima, MD, PhD, Atsuhiro Saito, PhD, Motoko Shiozaki, PhD, Naomasa Kawaguchi, PhD, Nariaki Matsuura, MD, PhD, Satoshi Nakatani, MD, PhD, Yoshiki Sakai, PhD, Takashi Daimon, PhD, Yutaka Okita, MD, PhD, Yoshiki Sawa, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 146, Issue 2, Pages 413-421 (August 2013) DOI: 10.1016/j.jtcvs.2012.10.003 Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 PCR and ELISA analysis in vitro showed that messenger RNA levels for HGF (A and D), VEGF (B and E), and SDF-1 (C and F) increased in a dose-dependent manner in NHDF cultured with ONO1301. PCR, Polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; NHDF, normal human dermal fibroblast; HGF, hepatocyte growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SDF-1, stromal-derived factor-1; VEGF, vascular endothelial growth factor. Mean ± standard error of the mean, respectively. The Journal of Thoracic and Cardiovascular Surgery 2013 146, 413-421DOI: (10.1016/j.jtcvs.2012.10.003) Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Echocardiography (A-F) showed ONO1301SR significantly improved distressed cardiac function. Note that ESWT/EDWT, reflecting on the radial strain of myocardium, was significantly more recovered in the ONO1301SR group than in the control group and that the clinical impact was more prominent in the target site after ONO1301SR treatment. Dd, End-diastolic dimension of the left ventricle; Ds, end-systolic dimension of the left ventricle; EF, ejection; ESWT, end-systolic wall thickness; EDWT, end-diastolic wall thickness. Mean ± standard error of the mean, respectively. Ind, induction of rapid pacing; Pre, before treatment of polylactic and glycolic acid polymer (PLGA) or ONO1301SR; Post, after treatment of PLGA or ONO1301SR. The Journal of Thoracic and Cardiovascular Surgery 2013 146, 413-421DOI: (10.1016/j.jtcvs.2012.10.003) Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Speckle-tracking echocardiography showed that the absolute values of peak radial, circumferential, and transverse strains at the target site in the ONO1301SR group were significantly higher than in the control group (A-D) while all of them but radial strains at the remote site in the ONO1301SR group and that in the control group were not significantly different (E-H), which implied that ONO1301SR had influence on the cardiac performance especially at the very site where ONO1301SR was administered; Radial, radial strain; Circumferential, circumferential strain; Transverse, transverse strain; Longitudinal, longitudinal strain. Target site is defined as the area in which ONO1301SR or glycolic acid polymer (PLGA) is injected while remote site as noninjection area. Ind, Induction of rapid pacing; Pre, before treatment of PLGA or ONO1301SR; Post, after treatment of PLGA or ONO1301SR. Mean ± standard error of the mean, respectively. The Journal of Thoracic and Cardiovascular Surgery 2013 146, 413-421DOI: (10.1016/j.jtcvs.2012.10.003) Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Histopathology; quantitative evaluation of interstitial fibrosis (A), mean cell diameter (B), vascular density (C), and representative micrograph of the Control group (D-G) and the ONO1301SR group (H-K). D and H, Hematoxylin and eosin staining. E and I, Masson trichrome staining. F and J, Sirius red staining. G and K, Staining with anti-human-von Willebrand factor. At the target site in the ONO1301SR group, the amounts of fibrosis and mean cell diameter were significantly smaller and vascular density was significantly higher than those in the control group and those at the remote site in the ONO1301SR group. Mean ± standard error of the mean, respectively. LV, Left ventricle; RV, right ventricle. The Journal of Thoracic and Cardiovascular Surgery 2013 146, 413-421DOI: (10.1016/j.jtcvs.2012.10.003) Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Electron microscopy revealed that the myocardium of the control group (A) showed prominent swelling or disruption of mitochondria, intracellular or perinuclear edema, and sarcoplasmic vacuoles resulting from dilation of sarcoplasmic reticulum (arrowhead). On the other hand, mitochondria in the ONO1301SR group (B) were compact and showed densely packed cristae. The Journal of Thoracic and Cardiovascular Surgery 2013 146, 413-421DOI: (10.1016/j.jtcvs.2012.10.003) Copyright © 2013 The American Association for Thoracic Surgery Terms and Conditions