Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT
| Autor: | Yoshiki Sawa, Shigeru Miyagawa, Tomomitsu Kanaya, Kenta Masada, Akima Harada, Yoshiki Sakai |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty lcsh:QH426-470 Cardiac fibrosis medicine.medical_treatment cardiac fibrosis Connective tissue Prostacyclin fibroblast 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Genetics medicine lcsh:QH573-671 Molecular Biology lcsh:Cytology prostacyclin business.industry Growth factor medicine.disease Vascular endothelial growth factor lcsh:Genetics 030104 developmental biology Endocrinology Cytokine medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Molecular Medicine Original Article Hepatocyte growth factor business ONO-1301 medicine.drug Transforming growth factor |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 19, Iss, Pp 210-219 (2020) |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2020.09.005 |
| Popis: | Fibroblast-to-myofibroblast transition (FMT) is the primary inducer of cardiac fibrosis. ONO-1301, a synthetic prostacyclin agonist, reportedly promotes tissue fibrosis repair by enhancing anti-fibrotic cytokine production. We hypothesized that ONO-1301 attenuates pressure-overloaded cardiac fibrosis by modulating FMT and generated a pressure-overloaded murine model via transverse aortic constriction (TAC) to evaluate the in vivo effects of ONO-1301. Cardiac fibrosis, left ventricular dilatation, and systolic dysfunction were established 4 weeks after TAC; however, ONO-1301 treatment initiated 2 weeks after TAC significantly attenuated those effects. Furthermore, ONO-1301 treatment significantly upregulated expression levels of cardioprotective cytokines such as vascular endothelial growth factor and hepatocyte growth factor in TAC hearts, whereas FMT-related factors, including transforming growth factor (TGF)-β1 and connective tissue growth factor, were significantly downregulated. The number of α-smooth muscle actin (α-SMA)- and vimentin-positive cells, representing fibroblast-originated cells transitioned into myofibroblasts, was significantly reduced in ONO-1301-treated TAC hearts. We isolated cardiac fibroblasts (CFs) from the left ventricles of adult male mice and assessed the effects of ONO-1301 on CFs stimulated by TGF-β. Results showed that ONO-1301 co-incubation significantly suppressed TGF-β-induced α-SMA expression and collagen synthesis, and significantly inhibited TGF-β-induced CF proliferation and migration. Our findings suggest that ONO-1301 ameliorates pressure overloaded cardiac fibrosis by inhibiting TGF-β-induced FMT. Graphical Abstract ONO-1301SR, a sustained-release drug-delivery system of a synthetic prostacyclin agonist, attenuates pressure overload-induced cardiac fibrosis by inhibiting TGF-β-induced fibroblast-to-myofibroblast transition in addition to enhancing the production of protective cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|