Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context
Background: We previously found that loss of lncRNA-AZIN2 splice variant (AZIN2-sv) increases cardiomyocyte (CM) proliferation and attenuates adverse ventricular remodelling post-myocardial infarction (MI). However, whether inhibition of AZIN2-sv can simultaneously induce angiogenesis and thus impro...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305723 |
| _version_ | 1818308394563403776 |
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| author | Xinzhong Li Yili Sun Senlin Huang Yanmei Chen Xiaoqiang Chen Mengsha Li Xiaoyun Si Xiang He Hao Zheng Lintao Zhong Yang Yang Wangjun Liao Yulin Liao Guojun Chen Jianping Bin |
| author_facet | Xinzhong Li Yili Sun Senlin Huang Yanmei Chen Xiaoqiang Chen Mengsha Li Xiaoyun Si Xiang He Hao Zheng Lintao Zhong Yang Yang Wangjun Liao Yulin Liao Guojun Chen Jianping Bin |
| author_sort | Xinzhong Li |
| collection | DOAJ |
| description | Background: We previously found that loss of lncRNA-AZIN2 splice variant (AZIN2-sv) increases cardiomyocyte (CM) proliferation and attenuates adverse ventricular remodelling post-myocardial infarction (MI). However, whether inhibition of AZIN2-sv can simultaneously induce angiogenesis and thus improve prognosis after MI is unclear. Methods: We used in situ hybridization and quantitative PCR to determine AZIN2-sv expression in endothelial cells. Knockdown and overexpression were performed to detect the role of AZIN2-sv in endothelial cell function, angiogenesis and prognosis after MI. RNA pulldown, RNA immunoprecipitation and luciferase reporter assays were used to determine the interaction with talin1 (Tln1) protein and miRNA-214 (miR-214). DNA pulldown and chromatin immunoprecipitation (ChIP) assays were used to study AZIN2-sv binding to upstream transcription factors. Findings: AZIN2-sv was enriched in cardiac endothelial cells. The loss of AZIN2-sv reduced endothelial cell apoptosis and promoted endothelial sprouting and capillary network formation in vitro. Moreover, in vivo, the loss of AZIN2-sv induced angiogenesis and improved cardiac function after MI. Mechanistically, AZIN2-sv reduced Tln1 and integrin β1 (ITGB1) protein levels to inhibit neovascularization. AZIN2-sv activated the ubiquitination-dependent degradation of Tln1 mediated by proteasome 26S subunit ATPase 5 (PSMC5). In addition, AZIN2-sv could bind to miR-214 and suppress the phosphatase and tensin homologue (PTEN)/Akt pathway to inhibit angiogenesis. With regard to the upstream mechanism, Bach1, a negative regulator of angiogenesis, bound to the promoter of AZIN2-sv and increased its expression. Interpretation: Bach1-activated AZIN2-sv could participate in angiogenesis by promoting the PSMC5-mediated ubiquitination-dependent degradation of Tln1 and blocking the miR-214/PTEN/Akt pathway. Inhibition of AZIN2-sv induced angiogenesis and myocardial regeneration simultaneously, thus, AZIN2-sv could be an ideal therapeutic target for improving myocardial repair after MI. Fund: National Natural Science Foundations of China. Keywords: AZIN2-sv, Angiogenesis, Tln1, Ubiquitination |
| first_indexed | 2024-12-13T07:13:35Z |
| format | Article |
| id | doaj.art-c0aaf9cc7aa04945b5f18d83e64f117b |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T07:13:35Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-c0aaf9cc7aa04945b5f18d83e64f117b2022-12-21T23:55:37ZengElsevierEBioMedicine2352-39642019-01-01396982Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in contextXinzhong Li0Yili Sun1Senlin Huang2Yanmei Chen3Xiaoqiang Chen4Mengsha Li5Xiaoyun Si6Xiang He7Hao Zheng8Lintao Zhong9Yang Yang10Wangjun Liao11Yulin Liao12Guojun Chen13Jianping Bin14Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.; Corresponding authors at: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.; Corresponding authors at: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.Background: We previously found that loss of lncRNA-AZIN2 splice variant (AZIN2-sv) increases cardiomyocyte (CM) proliferation and attenuates adverse ventricular remodelling post-myocardial infarction (MI). However, whether inhibition of AZIN2-sv can simultaneously induce angiogenesis and thus improve prognosis after MI is unclear. Methods: We used in situ hybridization and quantitative PCR to determine AZIN2-sv expression in endothelial cells. Knockdown and overexpression were performed to detect the role of AZIN2-sv in endothelial cell function, angiogenesis and prognosis after MI. RNA pulldown, RNA immunoprecipitation and luciferase reporter assays were used to determine the interaction with talin1 (Tln1) protein and miRNA-214 (miR-214). DNA pulldown and chromatin immunoprecipitation (ChIP) assays were used to study AZIN2-sv binding to upstream transcription factors. Findings: AZIN2-sv was enriched in cardiac endothelial cells. The loss of AZIN2-sv reduced endothelial cell apoptosis and promoted endothelial sprouting and capillary network formation in vitro. Moreover, in vivo, the loss of AZIN2-sv induced angiogenesis and improved cardiac function after MI. Mechanistically, AZIN2-sv reduced Tln1 and integrin β1 (ITGB1) protein levels to inhibit neovascularization. AZIN2-sv activated the ubiquitination-dependent degradation of Tln1 mediated by proteasome 26S subunit ATPase 5 (PSMC5). In addition, AZIN2-sv could bind to miR-214 and suppress the phosphatase and tensin homologue (PTEN)/Akt pathway to inhibit angiogenesis. With regard to the upstream mechanism, Bach1, a negative regulator of angiogenesis, bound to the promoter of AZIN2-sv and increased its expression. Interpretation: Bach1-activated AZIN2-sv could participate in angiogenesis by promoting the PSMC5-mediated ubiquitination-dependent degradation of Tln1 and blocking the miR-214/PTEN/Akt pathway. Inhibition of AZIN2-sv induced angiogenesis and myocardial regeneration simultaneously, thus, AZIN2-sv could be an ideal therapeutic target for improving myocardial repair after MI. Fund: National Natural Science Foundations of China. Keywords: AZIN2-sv, Angiogenesis, Tln1, Ubiquitinationhttp://www.sciencedirect.com/science/article/pii/S2352396418305723 |
| spellingShingle | Xinzhong Li Yili Sun Senlin Huang Yanmei Chen Xiaoqiang Chen Mengsha Li Xiaoyun Si Xiang He Hao Zheng Lintao Zhong Yang Yang Wangjun Liao Yulin Liao Guojun Chen Jianping Bin Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context EBioMedicine |
| title | Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context |
| title_full | Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context |
| title_fullStr | Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context |
| title_full_unstemmed | Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context |
| title_short | Inhibition of AZIN2-sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin-dependent talin1 degradation and activating the Akt pathwayResearch in context |
| title_sort | inhibition of azin2 sv induces neovascularization and improves prognosis after myocardial infarction by blocking ubiquitin dependent talin1 degradation and activating the akt pathwayresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418305723 |
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