Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats
Closure of the ductus arteriosus (DA) involves vasoconstriction and vascular remodeling. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, was reported with vasodilatory and anti-remodeling effects on pulmonary hypertensive vessels. However, its effects on DA are not understood. Therefore, we...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.661171/full |
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| author | Yu-Chi Hung Yu-Chi Hung Yi-Ching Liu Bin-Nan Wu Bin-Nan Wu Bin-Nan Wu Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jong-Hau Hsu Jong-Hau Hsu |
| author_facet | Yu-Chi Hung Yu-Chi Hung Yi-Ching Liu Bin-Nan Wu Bin-Nan Wu Bin-Nan Wu Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jong-Hau Hsu Jong-Hau Hsu |
| author_sort | Yu-Chi Hung |
| collection | DOAJ |
| description | Closure of the ductus arteriosus (DA) involves vasoconstriction and vascular remodeling. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, was reported with vasodilatory and anti-remodeling effects on pulmonary hypertensive vessels. However, its effects on DA are not understood. Therefore, we investigated whether cinaciguat regulated DA patency and examined its underlying mechanisms. In vivo, we found that cinaciguat (10 mg/kg, i.p. at birth) prevented DA closure at 2 h after birth with luminal patency and attenuated intimal thickening. These anti-remodeling effects were associated with enhanced expression of cyclic guanosine monophosphate (cGMP) in DA. Ex vivo, cinaciguat dilated oxygen-induced DA constriction dose-dependently. Such vasodilatory effect was blunted by KT-5823, a PKG inhibitor. In DA smooth muscle cells (DASMCs), we further showed that cinaciguat inhibited angiotensin II (Ang II)-induced proliferation and migration of DASMCs. In addition, cinaciguat inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production. Finally, Ang II-activated MAPKs and Akt were also inhibited by cinaciguat. In conclusion, cinaciguat prevents postnatal DA closure by vasodilation and anti-remodeling through the cGMP/PKG pathway. The mechanisms underlying anti-remodeling effects include anti-proliferation and anti-migration, with attenuation of mitochondrial ROS production, MAPKs, and Akt signaling. Thus, this study implicates that sGC activation may be a promising novel strategy to regulate DA patency. |
| first_indexed | 2024-12-19T02:11:13Z |
| format | Article |
| id | doaj.art-a508a5fd03a546dd98e20f92091e65cb |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-19T02:11:13Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-a508a5fd03a546dd98e20f92091e65cb2022-12-21T20:40:46ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-07-011210.3389/fphys.2021.661171661171Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal RatsYu-Chi Hung0Yu-Chi Hung1Yi-Ching Liu2Bin-Nan Wu3Bin-Nan Wu4Bin-Nan Wu5Jwu-Lai Yeh6Jwu-Lai Yeh7Jwu-Lai Yeh8Jwu-Lai Yeh9Jong-Hau Hsu10Jong-Hau Hsu11Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Pediatrics, St. Joseph Hospital, Kaohsiung, TaiwanDepartment of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medical Research, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medical Research, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, TaiwanDepartment of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanClosure of the ductus arteriosus (DA) involves vasoconstriction and vascular remodeling. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, was reported with vasodilatory and anti-remodeling effects on pulmonary hypertensive vessels. However, its effects on DA are not understood. Therefore, we investigated whether cinaciguat regulated DA patency and examined its underlying mechanisms. In vivo, we found that cinaciguat (10 mg/kg, i.p. at birth) prevented DA closure at 2 h after birth with luminal patency and attenuated intimal thickening. These anti-remodeling effects were associated with enhanced expression of cyclic guanosine monophosphate (cGMP) in DA. Ex vivo, cinaciguat dilated oxygen-induced DA constriction dose-dependently. Such vasodilatory effect was blunted by KT-5823, a PKG inhibitor. In DA smooth muscle cells (DASMCs), we further showed that cinaciguat inhibited angiotensin II (Ang II)-induced proliferation and migration of DASMCs. In addition, cinaciguat inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production. Finally, Ang II-activated MAPKs and Akt were also inhibited by cinaciguat. In conclusion, cinaciguat prevents postnatal DA closure by vasodilation and anti-remodeling through the cGMP/PKG pathway. The mechanisms underlying anti-remodeling effects include anti-proliferation and anti-migration, with attenuation of mitochondrial ROS production, MAPKs, and Akt signaling. Thus, this study implicates that sGC activation may be a promising novel strategy to regulate DA patency.https://www.frontiersin.org/articles/10.3389/fphys.2021.661171/fullductus arteriosussoluble guanylyl cyclaseremodelingvasoconstrictionvascular smooth muscle |
| spellingShingle | Yu-Chi Hung Yu-Chi Hung Yi-Ching Liu Bin-Nan Wu Bin-Nan Wu Bin-Nan Wu Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jwu-Lai Yeh Jong-Hau Hsu Jong-Hau Hsu Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats Frontiers in Physiology ductus arteriosus soluble guanylyl cyclase remodeling vasoconstriction vascular smooth muscle |
| title | Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats |
| title_full | Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats |
| title_fullStr | Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats |
| title_full_unstemmed | Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats |
| title_short | Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats |
| title_sort | cinaciguat prevents postnatal closure of ductus arteriosus by vasodilation and anti remodeling in neonatal rats |
| topic | ductus arteriosus soluble guanylyl cyclase remodeling vasoconstriction vascular smooth muscle |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.661171/full |
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