A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples.
BACKGROUND
Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling.


OBJECTIVE
We assessed the role of miR-145 in PAH.


RESULTS
We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice.


CONCLUSIONS
miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Paola
P
Caruso
Yvonne
Y
Dempsie
Hannah C
HC
Stevens
Robert A
RA
McDonald
Lu
L
Long
Ruifang
R
Lu
Kevin
K
White
Kirsty M
KM
Mair
John D
JD
McClure
Mark
M
Southwood
Paul
P
Upton
Mei
M
Xin
Eva
E
van Rooij
Eric N
EN
Olson
Nicholas W
NW
Morrell
Margaret R
MR
MacLean
Andrew H
AH
Baker
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D008168:Lung / Q000473:pathology / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs