Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline.
OBJECTIVE
MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown.


RESULTS
We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH.


CONCLUSIONS
Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention.
Caruso
Paola
P
Division of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Ave, University of Glasgow, Glasgow, Scotland.
MacLean
Margaret R
MR
Khanin
Raya
R
McClure
John
J
Soon
Elaine
E
Southgate
Mark
M
MacDonald
Robert A
RA
Greig
Jenny A
JA
Robertson
Keith E
KE
Masson
Rachel
R
Denby
Laura
L
Dempsie
Yvonne
Y
Long
Lu
L
Morrell
Nicholas W
NW
Baker
Andrew H
AH
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics*; D000860:Hypoxia / Q000150:complications / Q000235:genetics*; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism*; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics; D013997:Time Factors
C585349:MIRN322 microRNA, rat; D035683:MicroRNAs; D016686:Monocrotaline; D043244:Ribonuclease III