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 gammasecretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotalineinduced 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 monocrotalinetreated 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.