title: Enhanced store-operated Ca²+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats.
abstract: Pulmonary hypertension (PH) is associated with profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Previous studies show that canonical transient receptor potential (TRPC) genes are upregulated and store-operated Ca(2+) entry (SOCE) is augmented in PASMCs of chronic hypoxic rats and patients of pulmonary arterial hypertension (PAH). Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca(2+) influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd(3+), La(3+), and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca(2+) response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCT-induced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.
authors.affiliation: Department of Physiology and Pathophysiology, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Liu
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Rui-Xing
authors.initials: RX
authors.lastname: Wang
authors.forename: Yuan-Ning
authors.initials: YN
authors.lastname: Cao
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Yang
authors.forename: James S K
authors.initials: JS
authors.lastname: Sham
authors.forename: Mo-Jun
authors.initials: MJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage*; D009924:Organ Culture Techniques; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C096351:transient receptor potential cation channel, subfamily C, member 1; D016686:Monocrotaline; D002118:Calcium