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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
- Source :
- EBioMedicine, Vol 39, Iss , Pp 69-82 (2019)
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- 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
- Subjects :
- Medicine
Medicine (General)
R5-920
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 39
- Issue :
- 69-82
- Database :
- Directory of Open Access Journals
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.0aaf9cc7aa04945b5f18d83e64f117b
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.ebiom.2018.12.001