Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT
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 fibrosi...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-12-01
|
| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S232905012030190X |
| _version_ | 1818350498659434496 |
|---|---|
| author | Kenta Masada Shigeru Miyagawa Yoshiki Sakai Akima Harada Tomomitsu Kanaya Yoshiki Sawa |
| author_facet | Kenta Masada Shigeru Miyagawa Yoshiki Sakai Akima Harada Tomomitsu Kanaya Yoshiki Sawa |
| author_sort | Kenta Masada |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T18:22:48Z |
| format | Article |
| id | doaj.art-5803e440bd0544d38fcff98ca41e8f53 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-13T18:22:48Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-5803e440bd0544d38fcff98ca41e8f532022-12-21T23:35:40ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-12-0119210219Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMTKenta Masada0Shigeru Miyagawa1Yoshiki Sakai2Akima Harada3Tomomitsu Kanaya4Yoshiki Sawa5Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; Corresponding author: Yoshiki Sawa, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.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.http://www.sciencedirect.com/science/article/pii/S232905012030190XONO-1301prostacyclincardiac fibrosisfibroblast |
| spellingShingle | Kenta Masada Shigeru Miyagawa Yoshiki Sakai Akima Harada Tomomitsu Kanaya Yoshiki Sawa Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT Molecular Therapy: Methods & Clinical Development ONO-1301 prostacyclin cardiac fibrosis fibroblast |
| title | Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT |
| title_full | Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT |
| title_fullStr | Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT |
| title_full_unstemmed | Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT |
| title_short | Synthetic Prostacyclin Agonist Attenuates Pressure-Overloaded Cardiac Fibrosis by Inhibiting FMT |
| title_sort | synthetic prostacyclin agonist attenuates pressure overloaded cardiac fibrosis by inhibiting fmt |
| topic | ONO-1301 prostacyclin cardiac fibrosis fibroblast |
| url | http://www.sciencedirect.com/science/article/pii/S232905012030190X |
| work_keys_str_mv | AT kentamasada syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt AT shigerumiyagawa syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt AT yoshikisakai syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt AT akimaharada syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt AT tomomitsukanaya syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt AT yoshikisawa syntheticprostacyclinagonistattenuatespressureoverloadedcardiacfibrosisbyinhibitingfmt |