title: Isoquercitrin protects against pulmonary hypertension via inhibiting PASMCs proliferation.
abstract: Pulmonary vascular remodelling is a common feature among the heterogeneous disorders that cause pulmonary arterial hypertension (PAH), and pulmonary arterial smooth muscle cells (PASMCs) proliferation impact the long-term prognosis of the patient. Isoquercitrin (IQC) is a flavonoid with anti-oxidative, anti-inflammatory and anti-proliferative activations. This study aimed to investigate whether IQC could prevent PASMCs proliferation and vascular remodelling in monocrotaline (MCT) induced PAH. Male Wistar rats were administered with Vehicle or 0.1% IQC maintain feed after MCT (40 mg/kg) injection. Haemodynamic changes, right ventricular hypertrophy and lung morphological features were assessed 3 weeks later. MCT-induced PAH, pulmonary vascular remodelling and PASMCs proliferation in Vehicle-treated rats. IQC reduced the right ventricle systolic pressure (RVSP), the ratio of RV/LV+S and the RV hypertrophy. IQC significantly alleviated the expression of proliferating cell nuclear antigen (PCNA), smooth muscle α-actin (α-SMA), and the percentage of fully muscularized small arterioles. In vitro studies, PASMCs were pretreated with IQC and stimulated with platelet-derived growth factor (PDGF)-BB (20 ng/mL). IQC suppressed PDGF-BB-induced PASMCs proliferation and caused G0/G1 phase cell cycle arrest. IQC downregulated the expression of Cyclin D1 and CDK4 as well as inhibited p27Kip1 degradation. Meanwhile, IQC negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, Akt/GSK3β and ERK1/2. IQC ameliorated MCT-induced pulmonary vascular remodelling via suppressing PASMCs proliferation and blocking PDGF-Rβ signalling pathway.
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Centre for Reproductive Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Qin
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Chengmin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.|Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017208:Rats, Wistar; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D000975:Antioxidants; C530106:Ccnd1 protein, rat; C016527:isoquercitrin; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011794:Quercetin; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4
keywords: isoquercitrin; proliferation; pulmonary arterial smooth muscle cells; pulmonary hypertension