title: Upregulation of canonical transient receptor potential channel in the pulmonary arterial smooth muscle of a chronic thromboembolic pulmonary hypertension rat model.
abstract: Chronic ligation of the left main pulmonary artery (PA) results in pulmonary vascular remodeling and sustained vasoconstriction. This method has been used to generate a postobstructive pulmonary vasculopathy model to mimic severe chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the cellular and molecular mechanisms underlying CTEPH and to provide evidence for potential treatments. The CTEPH rat model was induced by surgical left PA ligation (LPAL). Right ventricular systolic pressure (RVSP), lung histochemistry and plasma D-dimer measurements were carried out to evaluate the model. A fluorescence microscope was used to measure the basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in rat distal pulmonary arterial smooth muscle cells through a Fura-2 fluorescence-based method. The expression of the canonical transient receptor potential channel 1 (TRPC1) and TRPC6 was determined by western blotting and real-time quantitative PCR in isolated distal pulmonary arteries (PA). At the time points of 2 and 5 weeks postsurgery, the RVSP showed significant increases in the LPAL groups in comparison with the respective control groups. LPAL also led to right ventricular hypertrophy (RVH), distal pulmonary arterial remodeling in unobstructed territories and persistently higher plasma D-dimer levels. Increases of the basal [Ca(2+)]i and SOCE in LPAL were associated with a clear upregulation of TRPC1 and TRPC6 expression in the distal PA. Our study demonstrated that LPAL successfully reproduced the vascular tone changes that mimic CTEPH pathogenesis. In this model, the increased RVSP and RVH are likely related to enhanced SOCE and upregulated TRPC1 and TRPC6 expression levels in the distal PA.
authors.affiliation: Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.|Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yun
authors.affiliation: Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.|Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wang
authors.affiliation: Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Wenju
authors.initials: W
authors.lastname: Lu
authors.affiliation: Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.|Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism*; D011655:Pulmonary Embolism / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D050052:TRPC Cation Channels; C492145:Trpc6 protein, rat; C036309:fibrin fragment D; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium