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Title: Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation

Highlights: • We focus on PASMCs proliferation in the pathogenesis of PAH. • Isorhynchophylline inhibited PASMCs proliferation and alleviated PAH. • IRN blocked PDGF-Rβ phosphorylation and its downstream signal transduction. • IRN regulated cyclins and CDKs to arrest cell cycle in the G0/G1 phase. • We reported IRN has the potential to be a candidate for PAH treatment. - Abstract: Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular + septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies,more » IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, ERK1/2, Akt/GSK3β, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and attenuate pulmonary vascular remodeling after MCT induction. These beneficial effects were at least through the inhibition of PDGF-Rβ phosphorylation and its downstream signaling pathways. Therefore, IRN might be a potential candidate for the treatment of PAH.« less
Authors:
;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ; ;  [1] ;  [2] ;  [3] ;  [6] ;  [1] ;  [2]
  1. Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012 (China)
  2. (China)
  3. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China)
  4. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060 (China)
  5. Department of Cardiology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai 200072 (China)
  6. Department of Respiratory, Qilu Hospital of Shandong University, Jinan 250012 (China)
Publication Date:
OSTI Identifier:
22416652
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 450; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; ALKALOIDS; ANTIGENS; CELL CYCLE; CONCENTRATION RATIO; DRUGS; FLUORESCENCE; GROWTH FACTORS; HYPERTENSION; HYPERTROPHY; IN VITRO; INHIBITION; MUSCLES; PATHOGENESIS; PHOSPHORYLATION; POLYCYCLIC AROMATIC HYDROCARBONS; RATS; TRANSCRIPTION; TRANSDUCERS