Inositol monophosphatase 1 as a novel interacting partner of RAGE in pulmonary hypertension.
Inositol monophosphatase 1 as a novel interacting partner of RAGE in pulmonary hypertension.
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DOI：
10.1152/ajplung.00393.2018
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发表时间：
2019-03
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通讯作者：
R. Rafikov;M. McBride;M. Zemskova;S. Kurdyukov;N. McClain;M. Niihori;P. Langlais;O. Rafikova
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作者：
R. Rafikov;M. McBride;M. Zemskova;S. Kurdyukov;N. McClain;M. Niihori;P. Langlais;O. Rafikova
肺动脉高压（PAH）是一种以进行性肺血管重塑为特征的致命疾病。晚期糖基化终末产物 (RAGE) 受体通过促进肺血管细胞增殖在 PAH 中发挥重要作用。 RAGE 还可以介导 Akt 信号传导的激活，但具体分子机制仍不清楚。本研究旨在确定 RAGE 的相互作用伙伴，其可以促进 RAGE 介导的 Akt 激活和 PAH 中的血管重塑。在 24 只雌性 Sprague-Dawley 大鼠（n = 8/组）中诱导进行性血管增生性 PAH，这些大鼠被随机分配为发生 PAH 1、2 或 5 周 [右心室收缩压 (RVSP) 分别为 56.5 ± 3.2、63.6 ± 1.6 和 111.1 ± 4.5 mmHg，对比 22.9 ±对照为 1.1 mmHg]。 PAH 引发大鼠肺部早期和晚期细胞凋亡，并伴有 RAGE 激活。质谱分析已确定 IMPA1 是 RAGE 的新型 PAH 特异性相互作用伙伴。邻近结扎试验 (PLA) 证实了肺动脉壁中 RAGE/IMPA1 复合物的形成。众所周知，6-磷酸葡萄糖 (G6P) 增加时 IMPA1 的激活在肌醇合成和回收中发挥着关键作用。事实上，我们证实从第 1 周开始，PAH 大鼠肺部的 G6P (P = 0.0005) 水平增加了三倍，这与磷脂酰肌醇 (3,4,5)-三磷酸 (PIP3) 的积累、PI3K 的膜易位以及膜 Akt 水平 (P = 0.02) 和 Akt 磷酸化增加了三倍相关。我们得出的结论是，新发现的 RAGE-IMPA1 复合物的形成可能与 PAH 中肌醇途径的刺激和 Akt 信号传导的激活有关。
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by progressive pulmonary vascular remodeling. The receptor for advanced glycation end products (RAGE) plays an important role in PAH by promoting proliferation of pulmonary vascular cells. RAGE is also known to mediate activation of Akt signaling, although the particular molecular mechanism remains unknown. This study aimed to identify the interacting partner of RAGE that could facilitate RAGE-mediated Akt activation and vascular remodeling in PAH. The progressive angioproliferative PAH was induced in 24 female Sprague-Dawley rats ( n = 8/group) that were randomly assigned to develop PAH for 1, 2, or 5 wk [right ventricle systolic pressure (RVSP) 56.5 ± 3.2, 63.6 ± 1.6, and 111.1 ± 4.5 mmHg, respectively, vs. 22.9 ± 1.1 mmHg in controls]. PAH triggered early and late episodes of apoptosis in rat lungs accompanied by RAGE activation. Mass spectrometry analysis has identified IMPA1 as a novel PAH-specific interacting partner of RAGE. The proximity ligation assay (PLA) confirmed the formation of RAGE/IMPA1 complex in the pulmonary artery wall. Activation of IMPA1 in response to increased glucose 6-phosphate (G6P) is known to play a critical role in inositol synthesis and recycling. Indeed, we confirmed a threefold increase in G6P ( P = 0.0005) levels in lungs of PAH rats starting from week 1 that correlated with accumulation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), membrane translocation of PI3K, and a threefold increase in membrane Akt levels ( P = 0.02) and Akt phosphorylation. We conclude that the formation of the newly discovered RAGE-IMPA1 complex could be responsible for the stimulation of inositol pathways and activation of Akt signaling in PAH.