Capsaicin-induced Ca(2+) signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH.

TitleCapsaicin-induced Ca(2+) signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH.
Publication TypeJournal Article
Year of Publication2017
AuthorsSong S, Ayon RJ, Yamamura A, Yamamura H, Dash S, Babicheva A, Tang H, Sun X, Cordery AG, Khalpey Z, Black SM, Desai AA, Rischard F, McDermott KM, Garcia JGN, Makino A, Yuan JX-J
JournalAm J Physiol Lung Cell Mol Physiol
Volume312
Issue3
PaginationL309-L325
Date Published2017 Mar 01
ISSN Number1522-1504
KeywordsAdult, Calcium Signaling, Capsaicin, Cell Proliferation, Chloride Channels, Cyclic AMP Response Element-Binding Protein, Diterpenes, Electric Conductivity, Extracellular Space, Familial Primary Pulmonary Hypertension, Female, Gene Knockdown Techniques, Humans, Hydrogen-Ion Concentration, Male, Middle Aged, Myocytes, Smooth Muscle, Osmosis, Phosphorylation, Potassium Channels, Pulmonary Artery, Temperature, TRPV Cation Channels, Up-Regulation
Abstract

<p>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 Ca(2+) concentration ([Ca(2+)]cyt). A rise in [Ca(2+)]cyt in 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 [Ca(2+)]cyt was 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 [Ca(2+)]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca(2+)]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca(2+)]cyt, and the hypo-osmolarity-induced rise in [Ca(2+)]cyt was 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 [Ca(2+)]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca(2+)]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 [Ca(2+)]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca(2+) influx and excessive PASMC proliferation in patients with IPAH.</p>

DOI10.1152/ajplung.00357.2016
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID27979859
PubMed Central IDPMC5374303
Grant ListP01 HL101902 / HL / NHLBI NIH HHS / United States
R01 HL060190 / HL / NHLBI NIH HHS / United States
R01 HL067841 / HL / NHLBI NIH HHS / United States
R01 HL136603 / HL / NHLBI NIH HHS / United States