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

, : Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. Plos One 10(9): E0137426-E0137426

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.


PMID: 26367462

DOI: 10.1371/journal.pone.0137426

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Shinde, V.K.; Joshi, P., 1985: Genetic analysis of height and maturity in tropical grain sorghum. Nonepistatic, epistatic digenic and epistatic trigenic interaction models were used to obtain least square estimates of various gene effects for plant height and days to flowering in 12 generations from 3 intervarietal crosses (VNL X ML, VNL X CSV...

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Weigel, R.J., 1981: Comments on "Static linear and nonlinear elastic properties of normal and arterialized venous tissue in dog and man" which appeared in Circ. Res. 37: 509-520, 1975. Circulation Research 49(6): 1363-1364

Hejna, P.; Safr, M.; Zátopková, L., 2013: Suicidal decapitation by guillotine: case report and review of the literature. Suicidal decapitation is seldom encountered in forensic medicine practice. This study reports the analysis of a suicide committed by a 31-year-old man with a self-fabricated guillotine. The construction of the guillotine was very interesting and s...

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Gupta, P.; Rohatgi, A.; Patel, S., 2016: Post-Partum Angiopathy presenting as Ischemic Stroke. NlmCategory="UNASSIGNED">Post-partum angiopathy is grouped within the category of reversible cerebral vasoconstriction syndromes. It is considered to be a rare but under-recognized cause of stroke especially in pregnancy. We present t...

Shiao, D.D.; Lumry, R.; Rajender, S., 1972: Modification of protein properties by change in charge. Succinylated chymotrypsinogen. European Journal of Biochemistry 29(2): 377-385

Gore, B.Z.; Caldwell, B.V.; Speroff, L., 1973: Estrogen-induced human luteolysis. Journal of Clinical Endocrinology and Metabolism 36(3): 615-617