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Hsa_circ_0016070/micro-340-5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1
Chun-Xia Huang1, Zhi-Xin Jiang2, Da-Yong Du2
1The Second School of Clinical Medicine Southern Medical University Guangzhou Guangdong Province China.
Insights
This study reveals that circ_0016070 exacerbates pulmonary hypertension (PH) by acting as a competing endogenous RNA for miR-340-5p. Inhibiting circ_0016070 may offer a therapeutic strategy for PH.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- RNA Biology
Background:
- Pulmonary hypertension (PH) is a severe condition often triggered by hypoxia.
- Understanding the molecular mechanisms underlying PH is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role and molecular mechanism of circ_0016070 in the development of pulmonary hypertension.
- To explore circ_0016070 as a potential therapeutic target for PH.
Main Methods:
- Real-time quantitative PCR to measure circ_0016070 expression in serum, cells, and animal models.
- Cellular assays (viability, migration, apoptosis) and molecular techniques (RIP, ChIP, dual-luciferase reporter assays) to elucidate mechanisms.
- Western blot, immunohistochemistry, and H&E staining to assess protein levels and pathological changes.
Main Results:
- circ_0016070 was significantly upregulated in PH models and patients.
- Downregulation of circ_0016070 attenuated PH progression, reducing proliferation and vascular remodeling while enhancing apoptosis.
- circ_0016070 acts as a competing endogenous RNA for miR-340-5p, promoting the TCF4/β-catenin/TWIST1 pathway.
Conclusions:
- circ_0016070 aggravates PH by sponging miR-340-5p and activating the TCF4/β-catenin/TWIST1 signaling pathway.
- circ_0016070 represents a promising therapeutic target for pulmonary hypertension.
Abstract:
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.
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