Search the Role of Pen-2 and Creb in the Inhibitory Effect of Propylthiouracil on Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by increased small pulmonary vascular resistance and caused by increased migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the mechanism underlying the pathogenesis of PAH remains unclear. Propylthiouracil (PTU), an antithyroid drug, has clinical implication in treating hyperthyroidism. Prior reports from our laboratory show that PTU, independent of its antithyroid action, may inhibit the development of atherogenesis in high cholesterol-fed rabbits and neointimal formation in balloon-injured rat carotid arteries. We also demonstrated that PTU inhibits VSMCs proliferation, migration, and converts vascular smooth muscle cells (VSMCs) from a serum-induced dedifferentiation state to a differentiated state. Interestingly, one report from the other group shows that PTU has an inhibitory effect on PAH development. However, the mechanisms underlying the suppressive effects of PTU on PAH remain to be clarified. Recently, a report showed that Notch, especially Notch3, signaling pathway is crucial for the development of PAH. In agreement with previous findings, our preliminary results indicated the essential role of Notch3 and its regulatory enzyme, gamma-secretase especially the Pen-2 subunit, in the inhibitory effect of PTU on monocrotaline-induced PAH rats. Furthermore, prior studies have associated cyclic AMP response element (CRE)-binding protein (CREB) with the pathogenesis of PAH. Some studies also demonstrate that there is a crosstalk between CREB and Pen-2 signals in other cells. Conceivably, we hypothesize that PTU inhibits PAH development and controls PASMC proliferation and migration via a crosstalk between Notch3/Pen-2 and CREB signaling pathways. In this study, we will focus on investigating the potential role of Pen-2 and CREB in the pathogenesis of PAH and the inhibitory effect of PTU on PAH formation. The aim of this study will therefore investigate whether: 1. PTU may affect CREB activation in monocrotaline-treated rats or hypoxic mice, in vivo. 2. PTU may affect CREB activation in cultured PASMCs, in vitro. 3. PTU may suppress PAH development via CREB inactivation. 4. there is a crosstalk between Pen-2 and CREB in the suppressive effect of PTU on PAH development. 5. there is a crosstalk between Pen-2 and CREB in the inhibitory effect of PTU on PASMC proliferation and migration. 6. PTU may affect PAH development in hypoxic CREB-/- mice.

Project ID:PC10601-0441
External Project ID:MOST104-2314-B182-051-MY3