ClC3 siRNA knockdown significantly reduced the excessive proliferation of pulmonary arterial smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.
Does ClC3 channel/transporter upregulation contribute to swelling-activated Cl− currents and excessive cell proliferation in IPAH-PASMCs?
Upregulated ClC3 channels/transporters contribute to swelling-activated Cl− currents and excessive proliferation of PASMCs in idiopathic pulmonary arterial hypertension, identifying them as a potential therapeutic target.
Absolute Event Rate: 0.67% vs 1%
p-value: p=<0.001
Pulmonary 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 small interfering RNA (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 present results indicate that upregulated ClC3 channels/transporters are involved in ICl-swell and the excessive proliferation of IPAH-PASMCs, thereby contributing to the pathogenesis of PAH. Therefore, ClC3 channels/transporters have potential as a target of therapeutic drugs for the treatment of PAH.
Amano et al. (Fri,) conducted a other in Idiopathic Pulmonary Arterial Hypertension. ClC3 siRNA knockdown vs. Control siRNA was evaluated on Cell proliferation of IPAH-PASMCs (BrdU incorporation relative to control) (p=<0.001). ClC3 siRNA knockdown significantly reduced the excessive proliferation of pulmonary arterial smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.