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

作者：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^*

来源：Circulation Research, 2012, 111(3): 290-300.

DOI：10.1161/CIRCRESAHA.112.267591

• pulmonary hypertension
• hypoxia
• molecular biology
• smooth muscle cells
• microRNA
• smooth muscle differentiation
• remodeling

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. %26lt;br%26gt;Objective: We assessed the role of miR-145 in PAH. %26lt;br%26gt;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. %26lt;br%26gt;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. (Circ Res. 2012;111:290-300.)

• 出版日期2012-7-20