title: Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs.
abstract: The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Wenju
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Meichan
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and.
authors.forename: Xin
authors.initials: X
authors.lastname: Duan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona;
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Division of Pulmonary Medicine, The People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China;
authors.forename: Dejun
authors.initials: D
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona; Division of Pulmonary Medicine, The People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China; jianwang1@email.arizona.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016686:Monocrotaline / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055415:Bone Morphogenetic Protein 4; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D050052:TRPC Cation Channels; D000069286:Bortezomib; D016686:Monocrotaline; D002118:Calcium
keywords: bortezomib; canonical transient receptor potential; intracellular calcium concentration; pulmonary hypertension; store-operated calcium entry