Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex
Background Hypoxia is considered a major leading cause of pulmonary hypertension (PH). In this study, the roles and molecular mechanism of circ_0016070 in PH were studied. Methods and Results The expression of circ_0016070 in serum samples, human pulmonary artery smooth muscle cells and hypoxia/mono...
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| Format: | Article |
| Language: | English |
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Wiley
2022-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.024147 |
| _version_ | 1797936018241880064 |
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| author | Chun‐Xia Huang Zhi‐Xin Jiang Da‐Yong Du Zhi‐Min Zhang Yang Liu Yun‐Tian Li |
| author_facet | Chun‐Xia Huang Zhi‐Xin Jiang Da‐Yong Du Zhi‐Min Zhang Yang Liu Yun‐Tian Li |
| author_sort | Chun‐Xia Huang |
| collection | DOAJ |
| description | Background Hypoxia is considered a major leading cause of pulmonary hypertension (PH). In this study, the roles and molecular mechanism of circ_0016070 in PH were studied. Methods and Results The expression of circ_0016070 in serum samples, human pulmonary artery smooth muscle cells and hypoxia/monocrotaline‐treated rats was determined by real‐time quantitative polymerase chain reaction. Cell viability, migration, and apoptosis were analyzed by Cell Counting Kit‐8, wound healing, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays, respectively. The molecular interactions were validated using RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assays. The levels of phenotype switch‐related proteins were evaluated by Western blot and immunohistochemistry. The pathological characteristics were assessed using hematoxylin and eosin staining. circ_0016070 was highly expressed in the serum samples, hypoxia‐induced pulmonary artery smooth muscle cells and pulmonary arterial tissues of PH rats. Downregulation of circ_0016070 ameliorated the excessive proliferation, migration, vascular remodeling, and phenotypic transformation but enhanced cell apoptosis in the PH rat model. In addition, micro (miR)‐340‐5p was verified as a direct target of circ_0016070 and negatively regulated TCF4 (transcription factor 4) expression. TCF4 formed a transcriptional complex with β‐catenin to activate TWIST1 (Twist family bHLH transcription factor 1) expression. Functional rescue experiments showed that neither miR‐340‐5p inhibition nor TWIST1 or TCF4 upregulation significantly impeded the biological roles of circ_0010670 silencing in PH. Conclusions These results uncovered a novel mechanism by which circ_0016070 play as a competing endogenouse RNA of miR‐340‐5p to aggravate PH progression by promoting TCF4/β‐catenin/TWIST1 complex, which may provide potential therapeutic targets for PH. |
| first_indexed | 2024-04-10T18:24:13Z |
| format | Article |
| id | doaj.art-26494a4f8d3e42fda28ca2182eefeb18 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T18:24:13Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-26494a4f8d3e42fda28ca2182eefeb182023-02-02T06:20:21ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-07-01111410.1161/JAHA.121.024147Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin ComplexChun‐Xia Huang0Zhi‐Xin Jiang1Da‐Yong Du2Zhi‐Min Zhang3Yang Liu4Yun‐Tian Li5The Second School of Clinical Medicine Southern Medical University Guangzhou Guangdong Province ChinaDepartment of Cardiology 305 Hospital of PLA Beijing ChinaDepartment of Cardiology 305 Hospital of PLA Beijing ChinaShanxi Medical University Linfen Peoples’ Hospital Linfen Shanxi Province ChinaDepartment of Cardiology 305 Hospital of PLA Beijing ChinaThe Second School of Clinical Medicine Southern Medical University Guangzhou Guangdong Province ChinaBackground Hypoxia is considered a major leading cause of pulmonary hypertension (PH). In this study, the roles and molecular mechanism of circ_0016070 in PH were studied. Methods and Results The expression of circ_0016070 in serum samples, human pulmonary artery smooth muscle cells and hypoxia/monocrotaline‐treated rats was determined by real‐time quantitative polymerase chain reaction. Cell viability, migration, and apoptosis were analyzed by Cell Counting Kit‐8, wound healing, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays, respectively. The molecular interactions were validated using RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assays. The levels of phenotype switch‐related proteins were evaluated by Western blot and immunohistochemistry. The pathological characteristics were assessed using hematoxylin and eosin staining. circ_0016070 was highly expressed in the serum samples, hypoxia‐induced pulmonary artery smooth muscle cells and pulmonary arterial tissues of PH rats. Downregulation of circ_0016070 ameliorated the excessive proliferation, migration, vascular remodeling, and phenotypic transformation but enhanced cell apoptosis in the PH rat model. In addition, micro (miR)‐340‐5p was verified as a direct target of circ_0016070 and negatively regulated TCF4 (transcription factor 4) expression. TCF4 formed a transcriptional complex with β‐catenin to activate TWIST1 (Twist family bHLH transcription factor 1) expression. Functional rescue experiments showed that neither miR‐340‐5p inhibition nor TWIST1 or TCF4 upregulation significantly impeded the biological roles of circ_0010670 silencing in PH. Conclusions These results uncovered a novel mechanism by which circ_0016070 play as a competing endogenouse RNA of miR‐340‐5p to aggravate PH progression by promoting TCF4/β‐catenin/TWIST1 complex, which may provide potential therapeutic targets for PH.https://www.ahajournals.org/doi/10.1161/JAHA.121.024147hsa_circ_0016070miR‐340‐5ppulmonary hypertensiontranscription factor 4TWIST1β‐catenin |
| spellingShingle | Chun‐Xia Huang Zhi‐Xin Jiang Da‐Yong Du Zhi‐Min Zhang Yang Liu Yun‐Tian Li Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease hsa_circ_0016070 miR‐340‐5p pulmonary hypertension transcription factor 4 TWIST1 β‐catenin |
| title | Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex |
| title_full | Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex |
| title_fullStr | Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex |
| title_full_unstemmed | Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex |
| title_short | Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex |
| title_sort | hsa circ 0016070 micro 340 5p axis accelerates pulmonary arterial hypertension progression by upregulating twist1 transcription via tcf4 β catenin complex |
| topic | hsa_circ_0016070 miR‐340‐5p pulmonary hypertension transcription factor 4 TWIST1 β‐catenin |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.024147 |
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