title: Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis.
abstract: Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca(2+) entry (SOCE) through store-operated Ca(2+) channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125-134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231-240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia-mediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Wenju
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Geisinger Medical Center, Danville, Pennsylvania.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hadadi
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Xin
authors.initials: X
authors.lastname: Yun
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
authors.forename: Meichan
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Respiratory Diseases, The Affiliated Hospital of Inner Mongolia Medical University Hohhot, Inner Mongolia, China; and.
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 Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona;
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 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
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
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D047495:PPAR gamma; C000613696:PPAR gamma, rat; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; D050052:TRPC Cation Channels; C492145:Trpc6 protein, rat; C096351:transient receptor potential cation channel, subfamily C, member 1; C024894:tanshinone II A sodium sulfonate; D017869:Cyclic GMP-Dependent Protein Kinases
keywords: PKG; PPAR-γ; SOCE; STS; TRPC