Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis.
Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis.
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2 型肌醇 1,4,5-三磷酸受体通过钙信号传导和细胞凋亡抑制肺动脉高压的进展。
DOI：
10.1007/s00380-018-1304-4
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发表时间：
2019
影响因子：
1.5
通讯作者：
Yamagishi H.
中科院分区：
文献类型：
--
作者：
Shibata A;Uchida K;Kodo K;Miyauchi T;Mikoshiba K;Takahashi T;Yamagishi H.
肺动脉高压（PAH）是一种与血管收缩和重构相关的进行性疾病。细胞内Ca2+信号调节肺动脉收缩和肺动脉平滑肌细胞（PASMCs）的增殖；然而，目前尚不清楚哪些与Ca2+信号相关的分子有助于PAH的进展。在这项研究中，我们发现了2型肌醇1,4,5-三磷酸受体（IP3R2），这是一个细胞内Ca2+释放通道，在小鼠PASMCs的sarco/内质网上特异性表达，并通过慢性缺氧诱导的PAH小鼠模型证明了其在PAH进展中的抑制作用。经超声心动图和右心室肥厚检测，IP3R2−/−小鼠慢性缺氧暴露后，PAH明显加重，免疫组化结果显示，IP3R2−/−小鼠的内侧壁厚度明显大于野生型小鼠。在慢性缺氧的IP3R2−/−小鼠PASMCs中，TUNEL实验显示凋亡明显抑制，而增殖无明显变化。基于体外荧光Ca2+成像，thapsigarin诱导的储存操作Ca2+进入（SOCE）在IP3R2−/−PASMCs中在常氧和缺氧条件下均显著增强。此外，添加基质相互作用分子(STIM) -Orai复合物抑制剂DPB162-AE可以显著抑制IP3R2−/−PASMCs中SOCE的增强，其抑制作用比2-APB强约100倍。我们的研究结果表明，IP3R2可能通过STIM-Orai途径促进PAH的凋亡和抑制SOCE，从而抑制PAH的进展。这些发现表明IP3R在PAH发展中的作用以前尚未确定，并可能有助于靶向治疗的发展。
Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca2+signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca2+signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP3R2), which is an intracellular Ca2+release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP3R2−/−mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP3R2−/−murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca2+entry (SOCE) was significantly enhanced in IP3R2−/−PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca2+imaging. Furthermore, the enhancement of SOCE in IP3R2−/−PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)–Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP3R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM–Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP3R in the development of PAH and may contribute to the development of targeted therapies.