MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension.
Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by increased medial and adventitial thickness of the lung vasculature. The underlying mechanisms that regulate the cell phenotype alteration during PPHN remodeling are largely unknown. We randomly selected newborn rats that were exposed to hypoxia (10-12%) or room air for 2 weeks and used a microarray to identify the lung tissue microRNAs (miRNAs) involved in PPHN progression. The role of a key miRNA that affects the endothelial-to-mesenchymal transition (EndMT) in primary cultured rat pulmonary microvascular endothelial cells (RPMECs) was investigated. The expression of miR-126a-5p was elevated in the PPHN model according to microarray analysis. The relative expression of miR-126a-5p in RPMECs increased when they were exposed to hypoxia (P<0.05), consistent with the microarray results. Pecam1 expression decreased, whereas alpha-smooth muscle actin (α-SMA) increased in the hypoxic RPMECs. Knockdown of miR-126a-5p in RPMECs followed by treatment with hypoxia for 48 h resulted in a significant increase in the expression of Pecam1 and a reduction in α-SMA expression, with a simultaneous increase in PI3K (p85β) and phosphorylation of AKT at serine 473 compared with the negative control. Finally, the circulating miR-126a-5p concentration was upregulated in the PPHN model compared with healthy neonates. We concluded that hypoxia changed the cell homeostasis and that miR-126a-5p was upregulated in PPHN, which is partly responsible for hypoxia-induced EndMT. The mechanism underlying the upregulation of miR-126a-5p by hypoxia probably acts through the p85-β/p-AKT pathway.
NICU, The Children's Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China.
Yan-Ping
YP
Xu
NICU, The Children's Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China.
Qi
Q
He
Center Lab, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zheng
Z
Shen
Center Lab, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xiao-Li
XL
Shu
NICU, The Children's Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China.
Chen-Hong
CH
Wang
Department of Neonatology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Jia-Jun
JJ
Zhu
NICU, The Children's Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China.
Li-Ping
LP
Shi
NICU, The Children's Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China.
Li-Zhong
LZ
Du
D000818:Animals; D000831:Animals, Newborn; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism; D035683:MicroRNAs / Q000097:blood*; D020411:Oligonucleotide Array Sequence Analysis; D010547:Persistent Fetal Circulation Syndrome / Q000097:blood / Q000209:etiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt