miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation
Yuan, Jason X.‐J.
Raj, J. Usha
AffiliationUniv Arizona, Dept Med
hypoxia-inducible factor 1
prolyl hydroxylase 2
pulmonary artery smooth muscle cell
smooth muscle cell
MetadataShow full item record
CitationmiR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation 2016, 5 (12):e004510 Journal of the American Heart Association
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AbstractBackground-Previously we found that smooth muscle cell (SMC)-specific knockout of miR-17 similar to 92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17 similar to 92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17 similar to 92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). Methods and Results-We show that hypoxic sm-17 similar to 92(-/-) mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm-17 similar to 92 (-/-) mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR-17 similar to 92 inhibitors suppress hypoxia-induced levels of HIF1 alpha, VEGF, Glut1, HK2, and PDK1 but not HIF2 alpha 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 HIF1a and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1 alpha 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 similar to 92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1 alpha.
NoteOpen Access Journal; Creative Commons Attribution Non-Commercial License
VersionFinal published version
SponsorsAmerican Lung Association Biomedical Research Grant [RG-416135]; Pulmonary Hypertension Association/Pfizer Proof-of-Concept Award; Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension Award; NIH [R01HL123804, R01HL115014]