title: Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation.
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, 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.
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; 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.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Cardiology, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Dachun
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Respiratory, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: qlliyu@126.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; 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. Electronic address: wdwu55@163.com.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000503:physiopathology* / Q000517:prevention & control*; D026121:Indole Alkaloids / Q000008:administration & dosage*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000078183:Oxindoles; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D026121:Indole Alkaloids; D000078183:Oxindoles; C052714:rhyncophylline
keywords: Isorhynchophylline; Platelet-derived growth factor; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells