This paper claims that the syntactic category of Japanese relative clauses can be larger than TP. The fact that Focus Particles can be found within Japanese relative clauses shows that the licenser, Focus-head, should be located at the CP-zone, adopting Rizzi’s (1997, 2004) cartographic analysis, on the assumption that Focus Particles can be licensed in situ. However, not every relative clause is larger than TP. We will present new data on Nominative/Genitive Conversion, which lead to a generalization that Focus Particles cannot appear in Japanese relative clauses where genitive subjects are allowed. This can be explained straightforwardly if we assume that Focus Phrase is missing in this type of relative clause. We will try to explore the mechanism of the case alternation phenomenon, with the refinement of Saito’s (2004) dichotomy of T (declarative T and adnominal T).

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Hepatic stellate cells (HSCs) are largely involved in hepatic fibrosis associated with liver diseases such as non-alcoholic steatohepatitis. An increase in cytosolic [Ca²⁺] in HSCs facilitates hepatic fibrosis, however, the regulatory mechanism is unclear. T-type voltage-dependent Ca²⁺ channels (T-VDCCs) contribute to neuronal transmission and cardiac rhythm in excitable cells. Recently, the pathophysiological roles of T-VDCCs in non-excitable cells such as cancer cells and immune cells have been focused. Under whole-cell patch-clamp configurations, transient inward currents were observed in mouse activated HSCs, but not in quiescent HSCs. Quantitative real-time PCR analysis revealed that the mRNA expression of T-VDCCs was significantly higher in activated HSCs than in quiescent HSCs. The viability of activated HSCs was significantly reduced by the treatment with T-VDCC inhibitors. These results suggest that the upregulation of T-VDCC expression in activated HSCs contributes to the regulation of Ca²⁺ signaling and cell proliferation. This study may contribute to the comprehensive understanding of HSC functions in hepatic fibrosis.

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Hepatic stellate cells are liver-specific pericytes that play central roles in the development of liver fibrosis. During liver injury, hepatic stellate cells transdifferentiate from the quiescent phenotype into the myofibroblast-like phenotype, resulting in high proliferation and extracellular matrix production. Large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels are expressed in many types of tissues and involved in the regulation of membrane potential, intracellular Ca²⁺ concentration, and cell proliferation. However, the involvement of BK_Ca channels on liver fibrosis remains unclear. In this study, we investigated the pathophysiological roles of BK_Ca channels in a human hepatic stellate cell line, LX-2. The mRNA expression analysis revealed that LX-2 cells highly expressed the α subunit of BK_Ca channels. In LX-2 cells, extracellular Ca²⁺ restoration in the presence of thapsigargin induced store-operated Ca²⁺ (SOC) entry, which potentially mediated by Orai/STIM channels. The SOC entry was significantly reduced by a specific inhibitor of BK_Ca channels, paxilline. In addition, the proliferation of LX-2 cells was clearly attenuated by paxilline. These results suggest that BK_Ca channels are functionally expressed in LX-2 cells and contribute to cell proliferation by regulating intracellular Ca²⁺ signaling.

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Pulmonary arterial hypertension (PAH) is classified as group 1 of pulmonary hypertension and designated intractable disease. The pathogenesis is mainly caused by vasoconstriction and vascular remodeling of the pulmonary artery. These abnormalities lead to sustained elevations in pulmonary arterial pressure and finally cause right heart failure. Several drugs have been recently developed, but those are mainly pulmonary vasodilators and ineffective for severe PAH. Therefore, novel drugs are awaited as therapeutic strategy of PAH. Previously, we found that the expression of sphingosine-1-phosphate (S1P) receptors was upregulated in PAH patients. Those modulator “fingolimod” blocked vascular remodeling and improved the survival rate of monocrotaline-induced pulmonary hypertensive (MCT-PH) rats. Fingolimod is an immunosuppressant drug that is used to treat multiple sclerosis, therefore, we herein examined whether fingolimod reduced inflammation in PAH. The accumulation of macrophages was detected in remodeled vascular legions of MCT-PH rats, which was reduced by the administration of fingolimod. In addition, fingolimod inhibited the proliferation of macrophages. Our results suggest that fingolimod ameliorates the development of PAH by blocking pulmonary vascular remodeling as a result of the reduction of inflammation.

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Melatonin is synthesized in and secreted from the pineal glands, which regulates the circadian rhythms. However, the effects of melatonin on pineal ion channels remains unclear. In the present study, the effects of melatonin on voltage-gated K⁺ (K_V) channels in rat pinealocytes were examined by whole-cell patch clamp configuration. The application of melatonin reduced pineal K_V currents in a concentration-dependent manner. Expression analysis revealed that K_V4.2 channels were highly expressed in rat pineal glands. In HEK293 cells expressed with K_V4.2 channels, melatonin decreased outward K_V4.2 currents. This inhibition was observed even in the presence of luzindole, an antagonist of melatonin receptors. Melatonin also blocked the activity of K_V4.3, K_V1.5 and K_V1.1 channels in reconstituted HEK293 cells. In pinealocytes treated with K_V4.2 siRNA, melatonin-sensitive K_V currents were attenuated. Furthermore, the application of melatonin caused membrane depolarization in rat pinealocytes. These results strongly suggest that melatonin directly inhibits K_V4.2 channels and results in membrane depolarization in rat pinealocytes.

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Hepatic stellate cells are liver-specific pericytes that play a critical role in the development of hepatic fibrosis. During liver injury, these cells transdifferentiate from the quiescent phenotype into the activated phenotype, resulting in enhanced cell proliferation and extracellular matrix production. The Ca²⁺ release-activated Ca²⁺ (CRAC) channels are expressed in many types of tissues and involved in the regulation of physiological and pathological processes. However, the involvement of CRAC channels on hepatic fibrosis remains unclear. In the present study, we investigated the pathophysiological roles of CRAC channels in human hepatic stellate LX-2 cells. Expression analysis revealed that LX-2 cells expressed Orai1 and STIM1 mRNAs which are the major components of CRAC channels. TGF-β1 caused the upregulation of myofibroblast markers, α-SMA and Col1α1, in LX-2 cells. The upregulation was markedly reduced by a non-specific CRAC channel blocker, BTP-2. BTP-2 clearly inhibited store-operated Ca²⁺ entry in LX-2 cells. In addition, BTP-2 significantly attenuated the proliferation of LX-2 cells. These results strongly suggest that CRAC channels are functionally expressed in hepatic stellate cells and contribute to extracellular matrix production and cell proliferation.

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Prolonged stress on blood vessels induces chronic inflammation, as well as the dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs), leading to vascular remodeling. Pressure overload, one of the major stresses causing vascular remodeling, depolarizes VSMCs and results in Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs). We have hypothesized that sustained depolarization induces excitation-transcription coupling (E-T coupling) in VSMCs and upregulates proinflammatory genes mainly using ex vivo preparations. To examine if sustained depolarization of VSMCs induced the E-T coupling and vascular remodeling in live mice, we utilized an optogenetic approach using mice expressing ChR2 specifically in smooth muscle (SMC-ChR2-YFP). We confirmed VSMC-specific expression of ChR2 in the carotid arteries of SMC-ChR2-YFP mice. Light stimulation successfully induced an increase in cytosolic [Ca²⁺] through VDCCs in VSMCs freshly isolated from mouse carotid arteries. Similar results were obtained in tissue preparations from carotid arteries. Furthermore, light stimulation of the carotid arteries in vivo induced pro-inflammatory gene transcription. These results suggest that sustained depolarization specific to VSMCs can cause E-T coupling in vivo and trigger vascular inflammation, which potentially lead to vascular remodeling.

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Hepatic stellate cells (HSC) are liver-specific fibroblasts that play a critical role in the development of hepatic fibrosis. During liver injury, these cells transdifferentiate into the activated phenotype, resulting in enhanced cell proliferation and extracellular matrix production. The functions of activated HSCs require an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt). However, the regulatory mechanisms underlying Ca²⁺ signaling in activated HSCs remain largely unknown. In the present study, the pathophysiological roles of calcium sensing receptors (CaSRs) were examined in human hepatic stellate cells LX-2. Expression analyses revealed that CaSR proteins were expressed in α-smooth muscle actin-positive LX-2 cells. Extracellular Ca²⁺ restoration (from 0 to 2.2 mM) increased [Ca²⁺]_cyt in LX-2 cells. The extracellular Ca²⁺-induced increase in [Ca²⁺]_cyt was reduced by the CaSR antagonists, 10µM NPS2143 and Calhex 231.TGF-β1 caused the upregulation of myofibroblast markers, α-SMA and Col1α1, in LX-2 cells. This upregulation was markedly reduced by NS2143. The treatment with NS2143 and Calhex 231 significantly attenuated the proliferation of LX-2 cells. These results indicate that CaSRs are functionally expressed in hepatic stellate cells and contribute to extracellular matrix production and cell proliferation.

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Pulmonary arterial hypertension (PAH) causes chronical increase in pulmonary artery pressure rises due to pulmonary vasoconstriction and vascular remodeling. Although several PAH drugs have been recently developed, no curative treatment has yet been achieved. Sustained elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) is closely associated to PAH pathogenesis such as enhanced contraction and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). [Ca²⁺]_cyt is regulated by membrane potentials which are partly regulated by voltage-dependent Cl^- channels. In the present study, the functional expression of voltage-dependent Cl^- channels (ClC family) was examined using PASMCs from normal subjects and idiopathic PAH (IPAH) patients. Expression analysis showed that ClC3 channel expression was increased in IPAH-PASMCs compared to normal-PASMCs. Swelling-activated Cl^- channel currents were larger in IPAH-PASMCs than in normal-PASMCs, which were attenuated by ClC3 siRNA. The growth of IPAH-PASMCs was inhibited by Cl^- channel blockers, niflumic acid and DIDS. ClC3 siRNA also decreased the proliferation of IPAH-PASMCs. In conclusion, the expression of ClC3 channels was upregulated in IPAH-PASMCs, resulting in excessive cell proliferation, which contributes to the pathogenesis of PAH.

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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the cardiovascular system. PAH is characterized by thickening of the pulmonary artery wall (remodeling) and often causes inflammation around the pulmonary artery. It has been reported that corosolic acid (CRA), is a pentacyclic triterpene acid contained in banaba leaves, has anti-inflammatory, anti-diabetic, and anti-cancer effects. In the present study, the effects of CRA on the pathogenesis of PAH were examined using monocrotaline (MCT)-induced pulmonary hypertensive (PH) rats. Male SD rats (4 weeks-old) were injected subcutaneously with vehicle (saline; control) or MCT (60 mg/kg). CRA (1 mg/kg) was administered intraperitoneally daily from 1 week after MCT injection. At 3 weeks after MCT injection, the effects of CRA on the in vivo parameters of PAH pathogenesis were analyzed. Hematoxylin and eosin (H&E) staining revealed that CRA clearly improved PAH remodeling in MCT-induced PH rats. The treatment with CRA also reduced the Fulton ratio (an index of right ventricular hypertrophy) in MCT-induced PH rats. Furthermore, CRA significantly lowered right ventricular systolic pressure (RVSP) in MCT-induced PH rats. In contrast, CRA did not affect these parameters in control rats. Taken together, CRA may be useful as a novel therapeutic candidate for PAH.

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Activated phonotype of hepatic stellate cells is associated with the development of liver fibrosis following enhanced Ca²⁺ signaling. Although cytosolic Ca²⁺ concentration is regulated by Ca²⁺ and K⁺ channels, their pathophysiological roles remain unclear. In the present study, we focused on the two-pore domain K⁺ (K_2P) channels, which regulate the resting membrane potentials, in hepatic stellate cells. In the presence of blockers for voltage-dependent K⁺ channels (10 mM tetraethylammonium and 5 mM 4-aminopyridine) and small-conductance Ca²⁺-activated K⁺ channels (100 nM apamin), outward K⁺ currents were detected in human hepatic stellate LX-2 cells. Expression analyses revealed that, among the K_2P family, TREK-1 (KCNK2) channels were abundantly expressed in LX-2 cells. TREK-1 siRNA (20 nM, for 48~72 h) specifically knocked-down the expression of TREK-1 channels. TREK-1 siRNA did not affect the expression of α-SMA (a marker for cell motility). On the other hand, TREK-1 siRNA reduced the expression of type I collagen (an extracellular matrix). TREK-1 siRNA also downregulated the expression of platelet-derived growth factor-BB (a cytokine associated with cell proliferation). These results suggest that TREK-1 channels contribute to the extracellular matrix production and cell proliferation in hepatic stellate cells.

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Background

Ca²⁺-activated Cl^- channels are expressed in smooth muscle, endothelial and secretory cells, and are involved in the smooth muscle contraction and cell growth and death. It has been reported that paxilline, a versatile inhibitor of big-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, suppresses Ca²⁺-activated Cl^- current, but the molecular mechanism of this suppression remains unclear. In this study, we focused on TMEM16A, which has been identified as a molecular entity of Ca²⁺-activated Cl^- channels and examined the pharmacological effects of paxilline on the Ca²⁺-activated Cl^- channel TMEM16A.

Method

The whole-cell patch clamp method was applied to HEK293 cells with steady-state expression of TMEM16A channel, and Ca²⁺-activated Cl^- current was measured.

Result

In TMEM16A-HEK293 cells, outward currents slowly activated by depolarization and inward trailing currents activated by repolarization were observed. The pharmacological effects of paxilline on TMEM16A channels were examined and found that 10 mM paxilline significantly suppressed the Ca²⁺-activated Cl^- current constituted by TMEM16A. The activation time constant of the outward current was increased by paxilline. Furthermore, the inhibitory effect of paxilline on TMEM16A channels was concentration dependent.

Summary

It has been shown that paxilline, a general-purpose BK_Ca channel inhibitor, suppresses Ca²⁺-activated Cl^- channels composed of TMEM16A. These findings may lead to the elucidation of the function of the Ca²⁺-activated Cl^- channel TMEM16A and targeted drug discovery.

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[Background] Macrophage (Mφ) is one of the innate immune cells and related to several chronic inflammatory diseases. Ionotropic purinergic P2X7 receptor plays a key role in the regulation of Mφ functions. Caveolin-1 (Cav-1) is known to modulate the activities of ion channels. In this study, the functional coupling between Cav-1 and P2X7 receptor was examined using Cav-1 knockout (Cav-1 KO) mice.

[Methods] Murine bone marrow-derived Mφ (BMDM) was used in this study. Molecular interaction between Cav-1 and P2X7 receptor was analyzed by proximal ligation assay (PLA). Intracellular [Ca²⁺] and [K⁺] were measured by confocal microscopy with each specific fluorescent indicator. Lytic cell death was analyzed by LDH assay.

[Results] In BMDMs, Cav-1 expression was increased by lipopolysaccharide. PLA revealed the molecular interaction between Cav-1 and P2X7 receptor. The treatment with 1 mM ATP evoked sustained Ca²⁺ influx and K⁺ efflux in BMDMs from wild-type mice. The response was enhanced in BMDMs from Cav-1 KO mice. ATP stimulation induced lytic cell death through P2X7 receptor activation, and this cell death was facilitated in Cav-1 KO mice.

[Conclusion] Cav-1 negatively regulates the activation of P2X7 receptors and results in cell death in Mφ. This study may lead to the development of novel drugs of chronic inflammatory diseases.

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[Background] Macrophage (Mφ) plays crucial roles in immunity and its dysfunction leads to the chronic inflammatory diseases such as arteriosclerosis. Several Mφ functions are modulated by the activation of ionotropic purinergic P2X7 receptor. Caveolin-1 (Cav-1) enables effective intracellular Ca²⁺ signaling by accumulating ion channels within caveolae domain. In this study, we analyzed the functional coupling between Cav-1 and P2X7 receptor using Cav-1 knockout (Cav-1 KO) mice.

[Methods] In murine bone marrow-derived Mφ (BMDM), the expression of Cav-1 was analyzed by real-time PCR and Western Blotting. Interaction of Cav-1 and P2X7 receptor was analyzed by proximal ligation assay. Ca²⁺ influx, K⁺ efflux and reactive oxygen species (ROS) production were measured with confocal microscopy. Cell death was analyzed by LDH assay.

[Results] The expression of Cav-1 was increased by LPS (lipopolysaccharide)-induced inflammatory stimulation in BMDM. Cav-1 was interacted with P2X7 receptor. Thereafter, ATP-evoked Ca²⁺ influx and K⁺ efflux were increased in Cav-1 KO BMDM. ROS production and cell death evoked by ATP were also enhanced in Cav-1 KO BMDM.

[Conclusion] Cav-1 suppresses the activation of P2X7 receptor and modulates immune responses in Mφ. This study may lead to the development of novel drugs for chronic inflammatory diseases.

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In vascular smooth muscles, the activity of Ca²⁺-activated Cl^- (Cl_Ca) channels regulates the membrane excitability and myogenic tone. TMEM16A channels are predominantly form Cl_Ca currents in vascular smooth muscles including portal vein smooth muscles (PVSMs). Caveola is a cholesterol-rich membrane invaginations and structurally contributes to effective and efficient signal transduction. Caveolin 1 (Cav1) is accumulated in the caveolin and plays a key role in forming the functional complex among enzymes, receptors, and ion channels. In this study, the functional roles of Cav1 on the expression and activity of TMEM16A Cl_Ca channels were examined in portal vein smooth muscle cells (PVSMCs) from wild-type (WT) and Cav1-knockout (KO) mice. Spontaneous contractions of PVSMs were recorded using an isotonic transducer. TMEM16A-mediated Cl_Ca currents were recorded by whole-cell patch-clamp configurations. The expression of TMEM16A channels was quantitatively analyzed by real-time PCR. The amplitude of spontaneous contractions of PVSMs was larger in Cav1-KO mice than WT mice. Whole-cell Cl_Ca currents were also larger in Cav1-KO PVSMCs than WT PVSMCs. Importantly, Ani9 (a specific blocker for TMEM16A channels)-sensitive currents were increased in Cav1-KO PVSMCs compared to WT PVSMCs. The expression of TMEM16A channels was higher in Cav1-KO PVSMs than WT PVSMs. The present data strongly suggest that the caveola structure formed by Cav1 negatively regulates the expression and activity of TMEM16A-mediated Cl_Ca channels in vascular smooth muscle cells.

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Ca²⁺-activated Cl⁻ (Cl_Ca) channels regulate membrane excitability and myogenic tone in vascular smooth muscles. TMEM16A-coding proteins are mainly responsible for functional Cl_Ca channels in vascular smooth muscles, including portal vein smooth muscles (PVSMs). Caveolae are cholesterol-rich and Ω-shaped invaginations on the plasma membrane that structurally contributes to effective signal transduction. Caveolin 1 (Cav1) accumulates in caveolae to form functional complexes among receptors, ion channels, and kinases. The present study examined the functional roles of Cav1 in the expression and activity of Cl_Ca channels in the portal vein smooth muscle cells (PVSMCs) of wild-type (WT) and Cav1-knockout (KO) mice. Contractile experiments revealed that the amplitude of spontaneous PVSM contractions was larger in Cav1-KO mice than WT mice. Under whole-cell patch-clamp configurations, Cl_Ca currents were markedly inhibited by 1 µM Ani9 (a selective TMEM16A Cl_Ca channel blocker) in WT and Cav1-KO PVSMCs. However, Ani9-sensitive Cl_Ca currents were significantly larger in Cav1-KO PVSMCs than in WT PVSMCs. Expression analyses showed that TMEM16A expression levels were higher in Cav1-KO PVSMs than in WT PVSMs. Therefore, the caveolar structure formed by Cav1 negatively regulates the expression and activity of TMEM16A-mediated Cl_Ca channels in vascular smooth muscle cells.

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Hepatic stellate cells (HSCs) play a significant role in the development of chronic liver diseases. Hepatic damage activates HSCs and results in hepatic fibrosis. The functions of activated HSCs require an increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt). However, the regulatory mechanisms underlying Ca²⁺ signaling in activated HSCs remain largely unknown. In the present study, functional analyses of Ca²⁺-sensing receptors (CaSRs) were performed using activated human HSCs, LX-2. Expression analyses revealed that CaSR proteins were expressed in α-smooth muscle actin-positive LX-2 cells. Extracellular Ca²⁺ restoration (from 0 to 2.2 mM) increased [Ca²⁺]_cyt in these cells. The extracellular Ca²⁺-induced increase in [Ca²⁺]_cyt was reduced by the CaSR antagonists, NPS2143 and Calhex 231. Furthermore, the growth of LX-2 cells was blocked by NPS2143 and Calhex 231 in concentration-dependent manners (IC₅₀ = 6.0 and 9.5 μM, respectively). LX-2 cell proliferation was also attenuated by NPS2143 and Calhex 231. In conclusion, CaSRs are functionally expressed in activated HSCs and regulate Ca²⁺ signaling and cell proliferation. The present results provide insights into the molecular mechanisms underlying hepatic fibrosis and will contribute to the development of potential therapeutic targets.

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Cerebral blood flow (ml/min/100g) (CBF) was detected by two methods, static xenon inhalation dynamic CT (Xe-CT) and perfusion CT, and a comparison of these two methods (Xe-CBF and perfusion CBF) was carried out in the same cases. Xe CT used 30% static xenon, 4 min wash-in, and 5 min wash-out, while perfusion CT was done by injecting 30 ml of non-ionic contrast medium at a rate of 9ml/sec. Forty-eight patients underwent these examinations (30 serious cases and 18 mild). The correlation coefficients in the hemispheric area were r=0.713 (p<0.01) with Xe-CBF and perfusion CBF in mild cases and r=0.567 (p<0.01) in serious cases. The two CBF values were especially disparate in serious cases. The value for perfusion CBF was almost double that of Xe-CBF in these cases. Perfusion CT was a useful examination for the detection of CBF, but in serious cases, CBF needs to be determined by Xe-CT as well.

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慢性関節リウマチ(以下RA)の肺合併症としての間質性肺炎(以下RA+IP)について, 肺局所病態を明らかにする目的で, soluble IL-2 receptor (以下sIL-2R)に注目して検討を行った. 気管支肺胞洗浄法(以下BAL)による肺局所細胞反応の検索では, RA+IPにおいて総細胞数の増加, リンパ球と顆粒球比率の増加を認めた. BAL液は10倍に濃縮し, 血清はそのままでELISA法によりsIL-2R並びにalbuminを測定した. RAでは血清中sIL-2Rが高値であり, RAの活動性としての赤沈値やランスバリー指数との間に正の相関が認められた. さらにRA+IPでは, RA自体の活動性や障害の程度にかかわらずより高値となる傾向であり, BAL液中におけるsIL-2R/albumin ratioも高値であったことから, 血清中において高値となるsIL-2Rは肺局所での活発な免疫応答を反映していると推察された.

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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 (I_Cl-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 I_Cl-swell. On the other hand, I_Cl-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 T16A_inh-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 I_Cl-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.

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