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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Paola Caruso
Paola Caruso (United Kingdom)
List of Authors: Paola Caruso, Yvonne Dempsie, Hannah Stevens, Robert A. McDonald, Lu Long, Ruifang Lu, Kevin White, Kirsty Mair, Mark Southwood, Paul Upton, Mei Xin, Eva van Rooij, Eric Olson, Nicholas W. Morrell, Margaret R. MacLean and Andrew H. Baker
Introduction: Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by extensive vascular remodeling, progressive elevation in pulmonary arterial pressure and premature death. MicroRNAs (miRNAs) are small non-coding RNAs that have the capacity to regulate gene expression post-transcriptionally by binding specific sequences within a target mRNA. In consideration of the role played by miRNAs in cell proliferation and vascular remodeling, we evaluated the involvement of the smooth muscle cell-associated miRNA miR-145 in the development of PAH. Methods & results: We first confirmed the smooth muscle cell-specific expression of miR-145 in mouse lung using in situ hybridization. In vivo, we observed a significant up-regulation of miR-145 in wild-type (wt) mice exposed to chronic hypoxia for 14 days. The progression of PAH was also evaluated in miR-145 knock-out (ko) mice via measurement of right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and percentage of remodeled pulmonary arteries. The genetic ablation of miR-145 resulted in protection against the development of the PAH in response to hypoxia. In patient samples, the analysis of the RNA extracted from the lung of patients with idiopathic and heritable PAH (iPAH and hPAH, respectively) revealed a significant increase in miR-145 expression, both in its pre- and mature form. A similar elevation of miR-145 was obtained analyzing the PASMCs obtained from hPAH patients with mutations in the bone morphogenetic protein type-2 receptor (BMPR2). In situ localization analysis demonstrated the presence of miR-145 selectively in the smooth muscle cell compartment in normal human lung as well as localization in vascular lesions in both iPAH and hPAH samples. Conclusion: Taken together, our data suggest a fundamental role for miR-145 in the development of PAH in the mouse hypoxic model as well as the presence of miR-145 in human PAH lesions. Manipulation of miR-145 may therefore represent a novel strategy to prevent the development of PAH.
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