ANGPTL8 is a negative regulator in pathological cardiac hypertrophy
Abstract Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like p...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05029-8 |
| _version_ | 1811287422443454464 |
|---|---|
| author | Lin Hu Jiarui Wei Yue Zhang Ziyuan Wang Junming Tang Jian Tang Yujiu Gao Xiaoqiao Zhang Yifan Li Yantong Liu Shinan Ma Xingrong Guo Qiufang Zhang |
| author_facet | Lin Hu Jiarui Wei Yue Zhang Ziyuan Wang Junming Tang Jian Tang Yujiu Gao Xiaoqiao Zhang Yifan Li Yantong Liu Shinan Ma Xingrong Guo Qiufang Zhang |
| author_sort | Lin Hu |
| collection | DOAJ |
| description | Abstract Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure. |
| first_indexed | 2024-04-13T03:18:10Z |
| format | Article |
| id | doaj.art-17d93aa4ba89495e900428b300c74ae5 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T03:18:10Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-17d93aa4ba89495e900428b300c74ae52022-12-22T03:04:50ZengNature Publishing GroupCell Death and Disease2041-48892022-07-0113711410.1038/s41419-022-05029-8ANGPTL8 is a negative regulator in pathological cardiac hypertrophyLin Hu0Jiarui Wei1Yue Zhang2Ziyuan Wang3Junming Tang4Jian Tang5Yujiu Gao6Xiaoqiao Zhang7Yifan Li8Yantong Liu9Shinan Ma10Xingrong Guo11Qiufang Zhang12Department of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineCollege of Pharmacy, Hubei University of medicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineDepartment of Pharmacology; Hubei Key Laboratory of Embryonic Stem Cell Research; and Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineAbstract Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.https://doi.org/10.1038/s41419-022-05029-8 |
| spellingShingle | Lin Hu Jiarui Wei Yue Zhang Ziyuan Wang Junming Tang Jian Tang Yujiu Gao Xiaoqiao Zhang Yifan Li Yantong Liu Shinan Ma Xingrong Guo Qiufang Zhang ANGPTL8 is a negative regulator in pathological cardiac hypertrophy Cell Death and Disease |
| title | ANGPTL8 is a negative regulator in pathological cardiac hypertrophy |
| title_full | ANGPTL8 is a negative regulator in pathological cardiac hypertrophy |
| title_fullStr | ANGPTL8 is a negative regulator in pathological cardiac hypertrophy |
| title_full_unstemmed | ANGPTL8 is a negative regulator in pathological cardiac hypertrophy |
| title_short | ANGPTL8 is a negative regulator in pathological cardiac hypertrophy |
| title_sort | angptl8 is a negative regulator in pathological cardiac hypertrophy |
| url | https://doi.org/10.1038/s41419-022-05029-8 |
| work_keys_str_mv | AT linhu angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT jiaruiwei angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT yuezhang angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT ziyuanwang angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT junmingtang angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT jiantang angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT yujiugao angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT xiaoqiaozhang angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT yifanli angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT yantongliu angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT shinanma angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT xingrongguo angptl8isanegativeregulatorinpathologicalcardiachypertrophy AT qiufangzhang angptl8isanegativeregulatorinpathologicalcardiachypertrophy |