title: Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats.
abstract: Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
authors.forename: Wen-Qun
authors.initials: WQ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, 410078, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. yuan_jianli@yahoo.com.
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D026121:Indole Alkaloids / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016278:Ventricular Function, Right / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D052999:Quinazolinones
chemical_list: D015740:Calcitonin Gene-Related Peptide; D050760:Cyclin-Dependent Kinase Inhibitor p27; D039621:Eukaryotic Initiation Factor-3; D026121:Indole Alkaloids; D011799:Quinazolines; D053773:Transforming Growth Factor beta1; C493962:Cdkn1b protein, rat; C508962:Tgfb1 protein, rat; C028632:rutecarpine; D052999:Quinazolinones
keywords: Calcitonin gene-related peptide; Cardiac fibroblasts; Right ventricular remodeling; Rutaecarpine; eIF3a; p27