RESEARCH ARTICLE Ion Channels and Transporters in Lung Function and Disease Capsaicin-induced Ca 2 (cid:2) signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH

Capsaicin-induced Ca 2 (cid:2) signaling is enhanced via upregulated TRPV1 channels in is an active component of and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca 2 (cid:2) concentration ([Ca 2 (cid:2) ] cyt ). A rise in [Ca 2 (cid: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 (cid: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 (cid:2) ] cyt ; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca 2 (cid: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 (cid:2) ] cyt , and the hypo-osmolarity-induced rise in [Ca 2 (cid: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 (cid:2) ] cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca 2 (cid:2) ] cyt , and capsaicin-induced CREB phosphorylation significantly enhanced in IPAH PASMCs normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca 2 (cid:2) ] cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca 2 (cid:2) influx and excessive PASMC proliferation in patients with IPAH.

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