title: BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs.
abstract: Multiple abnormalities of bone morphogenetic protein (BMPs) signaling are implicated in the process of pulmonary arterial hypertension (PAH). BMP4 plays an important role during the process of pulmonary arterial remodeling and mutant of the principle BMP4 receptor, BMP receptors II (BMPRII), is found to associate with the development of PAH. However, the likely mechanism defining the contribution of BMPRII to BMP4 mediated signaling in pulmonary arterial smooth muscle cells (PASMCs) remains comprehensively unclear. We previously found that enhanced store operated calcium entry (SOCE) and basal intracellular calcium concentration [Ca2+]i were induced by BMP4 via upregulation of TRPC1, 4 and 6 expression in PASMCs, and that BMP4 modulated TRPC channel expression through activating p38MAPK and ERK1/2 signaling pathways. In this study, BMPRII siRNA was used to knockdown BMPRII expression to investigate whether BMP4 upregulates the expression of TRPC and activating Smad1/5/8, ERK1/2 and p38MAPK pathway via BMPRII in distal PASMCs. Our results showed that knockdown of BMPRII: 1) attenuated BMP4 induced activation of P-Smad1/5/8, without altering BMP4 induced P-p38MAPK and P-ERK1/2 activation in PASMCs; 2) did not attenuate the BMP4-induced TRPC1, 4 and 6 expression; 3) did not affect BMP4-enhanced SOCE and basal [Ca2+]i. Thus, we concluded that BMP4 activated Smad1/5/8 pathway is BMPRII-dependent, while the BMP4 - ERK/p-P38 - TRPC - SOCE signaling axis are likely mediated through other receptor rather than BMPRII.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China; The 2nd Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Division of Pulmonary & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China; Division of Pulmonary & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Lichun
authors.initials: L
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yueqian
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, 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 Disease, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Laboratory Medicine, The 1st 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 Disease, Guangzhou Medical University, Guangzhou, Guangdong, China; Division of Pulmonary & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Pulmonary, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; D048051:p38 Mitogen-Activated Protein Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II