Upregulated ClC3 channels/transporters elicit swelling-activated Cl < sup > - < /sup > currents and induce excessive cell proliferation in idiopathic pulmonary arterial hypertension

Biol Pharm Bull. 2022 Aug 20. doi: 10.1248/bpb.b22-00513. Online ahead of print.ABSTRACTPulmonary arterial hypertension (PAH) is characterized by vascular remodeling of the pulmonary artery, which is mainly attributed to the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) comprising the medial layer of pulmonary arteries. The activity of ion channels associated with cytosolic Ca2+ signaling regulates the pathogenesis of PAH. Limited information is currently available on the role of Cl- channels in PASMCs. Therefore, the functional expression of ClC3 channels/transporters was herein investigated in the PASMCs of normal subjects and patients with idiopathic pulmonary arterial hypertension (IPAH). Expression analyses revealed the upregulated expression of ClC3 channels/transporters at the mRNA and protein levels in IPAH-PASMCs. Hypoosmotic perfusion (230 mOsm) evoked swelling-activated Cl- currents (ICl-swell) in normal-PASMCs, whereas 100 μM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) exerted the opposite effects. The siRNA knockdown of ClC3 did not affect ICl-swell. On the other hand, ICl-swell was larger in IPAH-PASMCs and inhibited by DIDS and the siRNA knockdown of ClC3. IPAH-PASMCs grew more than normal-PASMCs. The growth of IPAH-PASMCs was suppressed by niflumic acid and DIDS, but not by 9-anthracenecarboxylic acid or T16Ainh-A01. The siRNA knockdown of ClC3 also inhibited the proliferation of IPAH-PASMCs. Collectively, the presen...
Source: Biological and Pharmaceutical Bulletin - Category: Drugs & Pharmacology Authors: Source Type: research