Pulmonary artery hypertension (PAH) is a disease characterized by increased pulmonary artery (PA) resistance associated with pulmonary vascular remodeling, including proliferation of pulmonary artery smooth muscle cells (PASMCs) and formation of plexiform. Mutations in the gene encoding the bone morphogenetic protein (BMP) type II receptor (BMPRII) are associated with PAH(4-6), however a penetrance of BMPRII mutations is limited to ~20%, indicating that there are other factors contribute to the development of PAH. Aberrant expression and activation of the platelet derived growth factor (PDGF) signaling pathway are identified in the medial layer of the remodeled pulmonary arteries (PAs) from PAH patients and rodents treated with monocrotaline (MCT) or hypoxia. Administration of an antagonist of the PDGF receptor (imatinib mesylate) reverses PA remodeling in PAH animal models as well as clinical improvements in PAH patients. We demonstrated previously that the PDGF signal antagonizes the BMP signaling pathway in pulmonary artery smooth muscle cells (PASMCs) and promotes the "synthetic" phenotype characterized by increased proliferation, migration, and reduced contractility. We identified Tribbles homology 3 (Trb3) as a protein interacts with the carboxyl-terminus domain of BMPRII and essential for the BMP signaling pathway. We identified a small non-coding microRNA-24 (miR-24) which is potently induced upon stimulation with PDGF in PASMCs and targets Trb3. Increased expression of miR-24 leads to a degradation of Trb3 mRNA, hence the BMP-Smad signal, which promotes a switch from the contractile to the synthetic phenotype. Inhibition of miR- 24 prevents downregulation of the BMP-Smad signaling and the phenotype switch by PDGF). The objective of this application is to elucidate the mechanism that the PDGF-mediated induction of miR-24 contributes to the pathogenesis of PAH. The central hypothesis to be tested is that perturbation of the PDGF-miR-24 axis inhibits PA remodeling and mediates clinical improvement of the PAH phenotype through augmenting Trb3 and the BMP signaling pathway. In SA1, we will examine the efficacy of perturbation of the PDGF-mediated Trb3 regulation. In SA2, we will test the efficacy of perturbation of miR-24 in animal models of PAH. Finally, SA3 will demonstrate the deregulation of miR-24 in human PAH patients and identify novel targets of miR-24.
Pulmonary arterial hypertension (PAH) is a rare but terminal disease with a median survival rate of 2- 3 years from the time of diagnosis if left untreated. Thi application will investigate how PDGF signaling pathway contributes to the pathogenesis of PAH. The long-term goal of this application is to provide new targets for preventive or therapeutic interventions of PAH based on understanding the molecular mechanism of pathogenesis of PAH.
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