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.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by narrowing and obstruction of small pulmonary arteries with resulting in increased pulmonary vascular resistance and right ventricular hypertrophy, which may originate from dysfunction of pulmonary arterial smooth muscle cells (PASMCs) [1, 2]
Rats challenged with MCT developed PAH and RV hypertrophy, as indicated by increased right ventricular systolic pressure (RVSP) and RV/left ventricular (LV)+S weight ratio, respectively, at the 28th day after MCT injection compared with controls (Fig 1A)
Concomitant supplementation of PTU with T3 did not alter its suppressive effect on PAH development in MCT-treated rats, which precluded the involvement of its anti-thyroid
Summary
Pulmonary arterial hypertension (PAH) is characterized by narrowing and obstruction of small pulmonary arteries with resulting in increased pulmonary vascular resistance and right ventricular hypertrophy, which may originate from dysfunction of pulmonary arterial smooth muscle cells (PASMCs) [1, 2]. A prior study has demonstrated Notch to be a crucial pathway for PASMC dysfunction and PAH development [8]. The Notch receptor (Notch1-4) is an integral-membrane protein and can be activated by gamma-secretase cleavage to an intracellular domain (ICD) and the succeeding translocation into the nucleus [9]. Notch ICD acts as a transcript factor and regulates its downstream targets, such as hairy and enhancer-of-split (Hes), to affect SMC function [10,11]. Gamma-secretase is a protease complex in the cellular membrane consisting of presenilin 1 and 2 (PSEN1 and 2), nicastrin, anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen-2) subunits [12,13]. Inhibition of gamma-secretase function may block the activation of Notch signaling and have a potential effect on PASMC dysfunction and PAH formation
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