title: 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.affiliation: Department of Respiratory Therapy, Chang Gung University College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.affiliation: Cardiovascular Division, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
authors.affiliation: Department of Respiratory Therapy, Chang Gung University College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan; Division of Thoracic Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Cardiovascular Division, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D008297:Male; D053766:Presenilin-2 / Q000378:metabolism*; D011441:Propylthiouracil / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C498556:Notch3 protein, rat; D053766:Presenilin-2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011441:Propylthiouracil; D053829:Amyloid Precursor Protein Secretases