A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples.
Circ Res
; 111(3): 290-300, 2012 Jul 20.
Article
em En
| MEDLINE
| ID: mdl-22715469
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
MicroRNAs
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Modelos Animais de Doenças
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Hipertensão Pulmonar
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido