MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis
Abstract The detailed mechanism of pulmonary arteriovenous malformations after Glenn surgery (G-PAVMs) in cyanotic congenital heart disease (CHD) remains unclear. Microarray in situ hybridization was performed to assess the miRNA (miRNA) profiles of serum from pediatric patients (0–6 years of age) w...
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Nature Portfolio
2025-02-01
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| author | Junpei Kawamura Munekazu Yamakuchi Kentaro Ueno Teruto Hashiguchi Yasuhiro Okamoto |
| author_facet | Junpei Kawamura Munekazu Yamakuchi Kentaro Ueno Teruto Hashiguchi Yasuhiro Okamoto |
| author_sort | Junpei Kawamura |
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| description | Abstract The detailed mechanism of pulmonary arteriovenous malformations after Glenn surgery (G-PAVMs) in cyanotic congenital heart disease (CHD) remains unclear. Microarray in situ hybridization was performed to assess the miRNA (miRNA) profiles of serum from pediatric patients (0–6 years of age) with G-PAVMs and after the Fontan procedure without G-PAVMs. In addition, we investigated the tube formation, migration, and proliferation of human lung microvascular endothelial cells (HMVEC-L) transfected with miR-25-3p mimic, miR-25-3p inhibitor, or PHLPP2 small interfering RNA, and examined HIF-1α/VEGF-A signaling after hypoxic stimulation. Serum miRNAs that showed ≥ 2-fold higher levels in patients with G-PAVMs than in other patients were selected. MiR-25-3p was significantly upregulated in the pulmonary artery sera of the post-Glenn group than in the post-Fontan group. We identified PHLPP2 as a direct target of miR-25-3p. PHLPP2 expression was significantly decreased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells. HIF-1α and VEGF-A expression levels were increased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells in a PHLPP2/Akt/mTOR signaling-dependent manner after hypoxic stimulation. MiR-25-3p promoted HMVEC-L angiogenesis, proliferation, and migration under hypoxic conditions. MiR-25-3p in the pulmonary arteries may contribute to G-PAVM development. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-2a9f660bc95d4fcb92f9d8e2310ee8702025-02-09T12:28:33ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-88840-5MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axisJunpei Kawamura0Munekazu Yamakuchi1Kentaro Ueno2Teruto Hashiguchi3Yasuhiro Okamoto4Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima UniversityAbstract The detailed mechanism of pulmonary arteriovenous malformations after Glenn surgery (G-PAVMs) in cyanotic congenital heart disease (CHD) remains unclear. Microarray in situ hybridization was performed to assess the miRNA (miRNA) profiles of serum from pediatric patients (0–6 years of age) with G-PAVMs and after the Fontan procedure without G-PAVMs. In addition, we investigated the tube formation, migration, and proliferation of human lung microvascular endothelial cells (HMVEC-L) transfected with miR-25-3p mimic, miR-25-3p inhibitor, or PHLPP2 small interfering RNA, and examined HIF-1α/VEGF-A signaling after hypoxic stimulation. Serum miRNAs that showed ≥ 2-fold higher levels in patients with G-PAVMs than in other patients were selected. MiR-25-3p was significantly upregulated in the pulmonary artery sera of the post-Glenn group than in the post-Fontan group. We identified PHLPP2 as a direct target of miR-25-3p. PHLPP2 expression was significantly decreased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells. HIF-1α and VEGF-A expression levels were increased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells in a PHLPP2/Akt/mTOR signaling-dependent manner after hypoxic stimulation. MiR-25-3p promoted HMVEC-L angiogenesis, proliferation, and migration under hypoxic conditions. MiR-25-3p in the pulmonary arteries may contribute to G-PAVM development.https://doi.org/10.1038/s41598-025-88840-5Cyanotic CHDGlenn procedurePAVMmiR-25-3pPHLPP2 |
| spellingShingle | Junpei Kawamura Munekazu Yamakuchi Kentaro Ueno Teruto Hashiguchi Yasuhiro Okamoto MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis Scientific Reports Cyanotic CHD Glenn procedure PAVM miR-25-3p PHLPP2 |
| title | MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis |
| title_full | MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis |
| title_fullStr | MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis |
| title_full_unstemmed | MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis |
| title_short | MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis |
| title_sort | mir 25 3p regulates pulmonary arteriovenous malformation after glenn procedure in patients with univentricular heart via the phlpp2 hif 1α axis |
| topic | Cyanotic CHD Glenn procedure PAVM miR-25-3p PHLPP2 |
| url | https://doi.org/10.1038/s41598-025-88840-5 |
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