Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.

Abstract

Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

• Authors: Ying-Ju Lai, Gwo-Jyh Chang, Yung-Hsin Yeh, Jong-Hwei S Pang, Chung-Chi Huang, Wei-Jan Chen
• Journal: PloS one (PLoS One) Vol. 10 Issue 9 Pg. e0137426 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26367462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Notch3 protein, rat
• Presenilin-2
• Receptor, Notch3
• Receptors, Notch
• Propylthiouracil
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Gene Expression (drug effects)
• Hypertension, Pulmonary (metabolism)
• Lung (cytology)
• Male
• Presenilin-2 (metabolism)
• Propylthiouracil (pharmacology)
• Rats, Sprague-Dawley
• Receptor, Notch3
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)