title: Lipopolysaccharide potentiates endothelin-1-induced proliferation of pulmonary arterial smooth muscle cells by upregulating TRPC channels.
abstract: Lipopolysaccharide (LPS) and endothelin-1 (ET-1) are critical pathogenic factors in sepsis-induced pulmonary hypertension; however it is unknown whether they have a coordinated action in the pathogenesis of this disease. Here we found that although LPS did not change the contractility of rat pulmonary arterial smooth muscle cells (PASMCs) in response to ET-1, it significantly promoted ET-1-induced PASMC proliferation. Measurement of ET-1-evoked Ca(2+) transients in PASMCs showed that LPS dramatically enhanced Ca(2+) influx mediated by transient receptor potential canonical (TRPC) channels. LPS did not directly activate TRPC channels, instead it selectively upregulated the expression of TRPC3 and TRPC4 in pulmonary arteries. Small interfering RNA (siRNA) and chemical blockers against TRPC channels abolished LPS-induced PASMC proliferation. LPS-induced cell proliferation and TRPC expression was mediated by the Ca(2+)-dependent calcineurin/NFAT signaling pathway. We suggest that blocking TRPC channels could be an effective strategy in controlling pulmonary arterial remodeling after endotoxin exposure.
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China.
authors.forename: Hong-Ni
authors.initials: HN
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Medical Electrophysiology (Sichuan Medical University), Ministry of Education, and Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Medical Electrophysiology (Sichuan Medical University), Ministry of Education, and Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
authors.forename: Gui-Lan
authors.initials: GL
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Neurobiology, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lai
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China. Electronic address: lushaohua2010@126.com.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Lu
authors.affiliation: Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Pulmonary Medicine, Huadong Hospital, Fudan University School of Medicine, Shanghai, China. Electronic address: jmqu0906@163.com.
authors.forename: Jie-Ming
authors.initials: JM
authors.lastname: Qu
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D050051:Transient Receptor Potential Channels; D019703:Calcineurin
keywords: Endothelin-1; Lipopolysaccharide; PASMC; Proliferation; Pulmonary artery; TRPC channel