miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation
Background Previously we found that smooth muscle cell (SMC)‐specific knockout of miR‐17~92 attenuates hypoxia‐induced pulmonary hypertension. However, the mechanism underlying miR‐17~92‐mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR‐17~92 r...
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Wiley
2016-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004510 |
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| author | Tianji Chen Qiyuan Zhou Haiyang Tang Melike Bozkanat Jason X.‐J. Yuan J. Usha Raj Guofei Zhou |
| author_facet | Tianji Chen Qiyuan Zhou Haiyang Tang Melike Bozkanat Jason X.‐J. Yuan J. Usha Raj Guofei Zhou |
| author_sort | Tianji Chen |
| collection | DOAJ |
| description | Background Previously we found that smooth muscle cell (SMC)‐specific knockout of miR‐17~92 attenuates hypoxia‐induced pulmonary hypertension. However, the mechanism underlying miR‐17~92‐mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR‐17~92 regulates hypoxia‐inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). Methods and Results We show that hypoxic sm‐17~92−/− mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm‐17~92−/− mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR‐17~92 inhibitors suppress hypoxia‐induced levels of HIF1α, VEGF, Glut1, HK2, and PDK1 but not HIF2α in vitro in PASMC. Overexpression of miR‐17 in PASMC represses PHD2 expression, whereas miR‐17/20a inhibitors induce PHD2 expression. The 3′‐UTR of PHD2 contains a functional miR‐17/20a seed sequence. Silencing of PHD2 induces HIF1α and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1α and cell proliferation. SMC‐specific knockout of PHD2 enhances hypoxia‐induced vascular remodeling and exacerbates established pulmonary hypertension in mice. PHD2 activator R59949 reverses vessel remodeling in existing hypertensive mice. PHDs are dysregulated in PASMC isolated from pulmonary arterial hypertension patients. Conclusions Our results suggest that PHD2 is a direct target of miR‐17/20a and that miR‐17~92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1α. |
| format | Article |
| id | doaj-art-0590166fbbf34008baee1dc7dc1f8f55 |
| institution | DOAJ |
| issn | 2047-9980 |
| language | English |
| publishDate | 2016-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-0590166fbbf34008baee1dc7dc1f8f552025-08-20T02:44:20ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-12-0151210.1161/JAHA.116.004510miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell ProliferationTianji Chen0Qiyuan Zhou1Haiyang Tang2Melike Bozkanat3Jason X.‐J. Yuan4J. Usha Raj5Guofei Zhou6Department of Pediatrics University of Illinois at Chicago Chicago ILDepartment of Pediatrics University of Illinois at Chicago Chicago ILDepartment of Medicine University of Arizona Tucson AZDepartment of Pediatrics University of Illinois at Chicago Chicago ILDepartment of Medicine University of Arizona Tucson AZDepartment of Pediatrics University of Illinois at Chicago Chicago ILDepartment of Pediatrics University of Illinois at Chicago Chicago ILBackground Previously we found that smooth muscle cell (SMC)‐specific knockout of miR‐17~92 attenuates hypoxia‐induced pulmonary hypertension. However, the mechanism underlying miR‐17~92‐mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR‐17~92 regulates hypoxia‐inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). Methods and Results We show that hypoxic sm‐17~92−/− mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm‐17~92−/− mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR‐17~92 inhibitors suppress hypoxia‐induced levels of HIF1α, VEGF, Glut1, HK2, and PDK1 but not HIF2α in vitro in PASMC. Overexpression of miR‐17 in PASMC represses PHD2 expression, whereas miR‐17/20a inhibitors induce PHD2 expression. The 3′‐UTR of PHD2 contains a functional miR‐17/20a seed sequence. Silencing of PHD2 induces HIF1α and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1α and cell proliferation. SMC‐specific knockout of PHD2 enhances hypoxia‐induced vascular remodeling and exacerbates established pulmonary hypertension in mice. PHD2 activator R59949 reverses vessel remodeling in existing hypertensive mice. PHDs are dysregulated in PASMC isolated from pulmonary arterial hypertension patients. Conclusions Our results suggest that PHD2 is a direct target of miR‐17/20a and that miR‐17~92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1α.https://www.ahajournals.org/doi/10.1161/JAHA.116.004510hypoxiahypoxia‐inducible factor 1miR‐17˜92prolyl hydroxylase 2pulmonary artery smooth muscle cellpulmonary hypertension |
| spellingShingle | Tianji Chen Qiyuan Zhou Haiyang Tang Melike Bozkanat Jason X.‐J. Yuan J. Usha Raj Guofei Zhou miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease hypoxia hypoxia‐inducible factor 1 miR‐17˜92 prolyl hydroxylase 2 pulmonary artery smooth muscle cell pulmonary hypertension |
| title | miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation |
| title_full | miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation |
| title_fullStr | miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation |
| title_full_unstemmed | miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation |
| title_short | miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation |
| title_sort | mir 17 20 controls prolyl hydroxylase 2 phd2 hypoxia inducible factor 1 hif1 to regulate pulmonary artery smooth muscle cell proliferation |
| topic | hypoxia hypoxia‐inducible factor 1 miR‐17˜92 prolyl hydroxylase 2 pulmonary artery smooth muscle cell pulmonary hypertension |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004510 |
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