title: Capsaicin-induced Ca2+signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH.
abstract: Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+concentration ([Ca2+]cyt). A rise in [Ca2+]cytin pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca2+]cytwas significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca2+]cytincreases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca2+]cyt, and the hypo-osmolarity-induced rise in [Ca2+]cytwas greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca2+]cytincreases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt, and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca2+]cytincrease due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca2+influx and excessive PASMC proliferation in patients with IPAH.
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Ayon
authors.affiliation: Kinjo Gakuin University School of Pharmacy, Nagoya, Japan; and.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Swetaleena
authors.initials: S
authors.lastname: Dash
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Babicheva
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Xutong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Arlette G
authors.initials: AG
authors.lastname: Cordery
authors.affiliation: Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Zain
authors.initials: Z
authors.lastname: Khalpey
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.affiliation: Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Franz
authors.initials: F
authors.lastname: Rischard
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: McDermott
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; jasonyuan@email.arizona.edu.|Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.|Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000328:Adult; D020013:Calcium Signaling / Q000187:drug effects*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D004553:Electric Conductivity; D005110:Extracellular Space / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009995:Osmosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*; D050916:TRPV Cation Channels / Q000378:metabolism*; D013696:Temperature; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018118:Chloride Channels; D017362:Cyclic AMP Response Element-Binding Protein; D004224:Diterpenes; D015221:Potassium Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C468130:iodoresiniferatoxin; C071423:capsazepine; D002211:Capsaicin
keywords: TRPV1; capsaicin; idiopathic pulmonary arterial hypertension; mechanosensitive cation channels; osmotic pressure