Hydrogen sulfide regulates cardiac sarcoplasmic reticulum Ca2+ uptake via KATP channel and PI3K/Akt pathway
Hydrogen sulfide regulates cardiac sarcoplasmic reticulum Ca2+ uptake via KATP channel and PI3K/Akt pathway
复制标题
硫化氢通过 K(ATP) 通道和 PI3K/Akt 途径调节心脏肌浆网 Ca(2) 摄取。
DOI：
10.1016/j.lfs.2012.07.026
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发表时间：
2012-09-17
期刊：
影响因子：
6.1
通讯作者：
Geng, Bin
中科院分区：
文献类型：
--
作者：
Chen, Yu;Zhao, Jing;Geng, Bin
目的：探讨硫化氢（H2S）对大鼠心脏肌浆网（SR）钙摄取活性的影响及可能的信号传导。主要方法：经H2S处理后分离粗SR，然后采用同位素示踪法测定SR Ca2+摄取和SR Ca2+-ATP酶（SERCA）活性。通过特定阻断剂分析了 K-ATP 通道、PI3K/Akt 和 SR 膜蛋白受磷蛋白 (PLB) 途径的可能作用，并通过测量蛋白磷酸化来测定靶蛋白激活。 主要发现：外源 H2S 降低了 SR 时间或浓度依赖性的 Ca2+ 摄取，这与 SERCA 活性降低有关。通过 DL-炔丙基甘氨酸抑制内源 H2S 产生可增加 SR Ca2+ 吸收和 SERCA 活性。 H2S 对 PLB 磷酸化的抑制是通过 SERCA 活性实现的，并可被两种 PI3K 抑制剂（渥曼青霉素和 LY294002）逆转。格列本脲（一种 K-ATP 通道阻滞剂）可阻断 H2S 对 PLB 和 Akt 磷酸化的抑制作用。 Pinacidil（一种 K-ATP 通道开放剂）可降低 PLB 的磷酸化并逆转 DL-炔丙基甘氨酸的作用。 H2S 预处理增加了 PLB 磷酸化，但不影响 SERCA 活性。意义：由于 PI3K/Akt 或 K-ATP 通道下调与 PLB 磷酸化相关的 SERCA 活性，内源性 H2S 短暂且可逆地抑制大鼠心脏 SR 中 SR Ca2+ 的摄取。 SR Ca2+摄取和L型Ca2+通道的短暂负调节有助于Ca2+循环稳态，这可能是缺血性疾病的重要分子机制。 Crown 版权所有 (C) 2012 由 Elsevier Inc. 出版。保留所有权利。
Aims: To investigate the effects of hydrogen sulfide (H2S) on calcium uptake activity of the rat cardiac sarcoplasmic reticulum (SR) and possible signaling.Main methods: Crude SR was isolated after treatment with H2S, then SR Ca2+ uptake and SR Ca2+-ATPase (SERCA) activity was measured by the isotopic tracer method. The possible roles of the K-ATP channel and PI3K/Akt and SR-membrane protein phospholamban (PLB) pathway were analyzed by specific blockers, and target protein activation was assayed by measuring protein phosphorylation.Key findings: Exogenous H2S lowered Ca2+ uptake into the SR time or concentration dependently, which was associated with decreased SERCA activity. Inhibiting endogenous H2S production by DL-propargylglycine increased SR Ca2+ uptake and SERCA activity. H2S inhibition of PLB phosphorylation was through SERCA activity and was reversed by two PI3K inhibitors, wortmannin and LY294002. Glibenclamide (a K-ATP, channel blocker) blocked the inhibitory effects of H2S on PLB and Akt phosphorylation. Pinacidil (a K-ATP channel opener) reduced the phosphorylation of PLB and reversed the effects of DL-propargylglycine. H2S preconditioning increased PLB phosphorylation but did not affect SERCA activity.Significance: Endogenous H2S transiently and reversibly inhibits SR Ca2+ uptake in rat heart SR because of downregulated SERCA activity associated with PLB phosphorylation by the PI3K/Akt or K-ATP channel. The transient negative regulation of SR Ca2+ uptake and the L-type Ca2+ channel contributes to Ca2+ cycle homeostasis, which might be an important molecular mechanism in ischemic diseases. Crown Copyright (C) 2012 Published by Elsevier Inc. All rights reserved.