A Role for miR-145 in Pulmonary Arterial Hypertension: Evidence From Mouse Models and Patient Samples

• Published in: Circulation research 2012-07, Vol.111 (3), p.290-300
• Main Authors: Caruso, Paola, Dempsie, Yvonne, Stevens, Hannah C, McDonald, Robert A, Long, Lu, Lu, Ruifang, White, Kevin, Mair, Kirsty M, McClure, John D, Southwood, Mark, Upton, Paul, Xin, Mei, van Rooij, Eva, Olson, Eric N, Morrell, Nicholas W, MacLean, Margaret R, Baker, Andrew H
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; Down-Regulation - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Knock-In Techniques; Humans; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - prevention & control; Lung - pathology; Lung - physiology; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - physiology; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.112.267591

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.