title: Inhibition of Notch3 prevents monocrotaline-induced pulmonary arterial hypertension.
abstract: It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Yonghong
authors: Y
authors: Zhang
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Xinming
authors: X
authors: Xie
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Yanting
authors: Y
authors: Zhu
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Lu
authors: L
authors: Liu
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Wei
authors: W
authors: Feng
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Yilin
authors: Y
authors: Pan
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Cui
authors: C
authors: Zhai
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Rui
authors: R
authors: Ke
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Shaojun
authors: S
authors: Li
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Yang
authors: Y
authors: Song
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Yuncun
authors: Y
authors: Fan
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Fenling
authors: F
authors: Fan
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Xiaochuang
authors: X
authors: Wang
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Fengjuan
authors: F
authors: Li
authors: a Department of Respiratory Medicine, the First Affiliated Hospital of Medical College at Xi'an JiaoTong University , Xi'an , Shanxi , China.
authors: Manxiang
authors: M
authors: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C498556:Notch3 protein, rat; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D016686:Monocrotaline
keywords: Hes1; Notch3; P27Kip1; Skp2; pulmonary arterial hypertension; vascular remodeling