CRYAB and HSPB2 deficiency increases myocyte mitochondrial permeability transition and mitochondrial calcium uptake
CRYAB and HSPB2 deficiency increases myocyte mitochondrial permeability transition and mitochondrial calcium uptake
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DOI：
10.1016/j.yjmcc.2006.03.003
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发表时间：
2006-06-01
影响因子：
5
通讯作者：
Benjamin, Ivor J.
中科院分区：
文献类型：
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作者：
Kadono, Toshie;Zhang, Xiu Quan;Benjamin, Ivor J.
小热休克蛋白 CRYAB 和 HSPB2 的双敲除 (DKO) 会增加体外缺血/再灌注 (I/R) 诱导的坏死和细胞凋亡，但所涉及的机制尚不清楚。我们检查了 [Ca2+](i) 期间暴露于升高的 [Ca2+](i) 引起的 [Ca2+](m) 的代谢抑制 (MI) 变化，以及分离的 DKO 心室肌细胞 (VM) 中的线粒体是否比野生型 (WT) 更容易诱导线粒体通透性转变 (MPT)。代谢抑制 (MI) 期间 DKO 肌细胞中 [Ca2+](i) 的增加小于 WT，哇巴因导致 DKO 中 [Ca2+](m) 的增加比 WT 更大。这些结果表明 DKO 肌细胞线粒体中 Ca2+ 的摄取增加。将透化 VM 暴露于 1000 nM [Ca2+] 5 分钟期间测量 Rhod 2 荧光，证实 DKO 肌细胞增强了线粒体 Ca2+ 摄取，并且通过抑制 NO 合成消除了 DKO 和 WT 肌细胞线粒体之间的这种差异。 DKO 肌细胞中的 MPT 比 WT 更容易被哇巴因、PAO 或 TMRM 诱导。因此，DKO VM 中线粒体对 Ca2+ 的吸收通过 NO 依赖性机制增加。这可能导致 MPT 的发展，并增加 I/R 期间的 VM 损伤。这些发现表明 CRYAB 和/或 HSPB2 在线粒体功能中发挥重要作用。 (c) 2006 Elsevier Inc. 保留所有权利。
Double knockout (DKO) of the small heat shock proteins CRYAB and HSPB2 increases necrosis and apoptosis induced by ischemia/reperfusion (I/R) in vitro, but the mechanisms involved are unknown. We examined [Ca2+](i) during metabolic inhibition (MI) changes in [Ca2+](m) induced by exposure to elevated [Ca2+](i), and whether mitochondria in isolated DKO ventricular myocytes (VM) are more susceptible than wild type (WT) to induction of the mitochondrial permeability transition (MPT). The rise in [Ca2+](i) in DKO myocytes during metabolic inhibition (MI) was less than in WT, and ouabain caused a greater increase in [Ca2+](m) in DKO than in WT These findings suggested that Ca2+ uptake was increased in mitochondria in DKO myocytes. Measurements of Rhod 2 fluorescence during exposure of permeabilized VM to 1000 nM [Ca2+] for 5 min confirmed that DKO myocytes have enhanced mitochondrial Ca2+ uptake, and this difference between DKO and WT myocyte mitochondria was eliminated by inhibition of NO synthesis. MPT was induced more readily by ouabain, PAO, or TMRM in DKO myocytes than in WT. Thus, Ca2+ uptake by mitochondria is increased in DKO VM by a NO-dependent mechanism. This can predispose to the development of MPT, and increased VM injury during I/R. These findings indicate an important role of CRYAB and/or HSPB2 in mitochondrial function. (c) 2006 Elsevier Inc. All rights reserved.