TY - JOUR
T1 - A role for miR-145 in pulmonary arterial hypertension
T2 - Evidence from mouse models and patient samples
AU - Caruso, Paola
AU - Dempsie, Yvonne
AU - Stevens, Hannah C.
AU - McDonald, Robert A.
AU - Long, Lu
AU - Lu, Ruifang
AU - White, Kevin
AU - Mair, Kirsty M.
AU - McClure, John D.
AU - Southwood, Mark
AU - Upton, Paul
AU - Xin, Mei
AU - Van Rooij, Eva
AU - Olson, Eric N.
AU - Morrell, Nicholas W.
AU - MacLean, Margaret R.
AU - Baker, Andrew H.
PY - 2012/7/20
Y1 - 2012/7/20
N2 - RATIONALE:: 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. METHODS AND 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.
AB - RATIONALE:: 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. METHODS AND 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.
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U2 - 10.1161/CIRCRESAHA.112.267591
DO - 10.1161/CIRCRESAHA.112.267591
M3 - Article
C2 - 22715469
AN - SCOPUS:84864229176
SN - 0009-7330
VL - 111
SP - 290
EP - 300
JO - Circulation research
JF - Circulation research
IS - 3
ER -