Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes.
Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes.
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DOI：
10.1016/j.ceca.2009.06.002
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发表时间：
2009-08
期刊：
影响因子：
4
通讯作者：
Niggli E
中科院分区：
文献类型：
--
作者：
Fanchaouy M;Polakova E;Jung C;Ogrodnik J;Shirokova N;Niggli E
在杜氏肌营养不良症中，细胞骨架蛋白营养不良蛋白的缺乏导致骨骼肌缺陷，但也导致扩张性心肌病，约占死亡率的20%。导致心肌细胞死亡和心肌病的机制尚不清楚。一种假说认为，缺乏肌营养不良蛋白会导致机械应力期间膜不稳定，并激活Ca2+进入途径。使用从营养不良mdx小鼠分离的心肌细胞，我们用药理学工具解剖了各种假定的Ca2+内流途径的贡献。细胞质内Ca2+和Na+信号以及膜不含化合物的摄取用荧光指示器使用共聚焦显微镜和光度法监测。膜应力作为中等渗透挑战，膜电流采用全细胞膜片钳技术进行定量。我们的研究结果表明，两种主要的Ca2+内流途径，拉伸激活的膜通道和短暂的微破裂的主要贡献。此外，我们发现了次要Ca2+内流途径的证据，即Na+-Ca2+交换（NCX），其在心肌中具有较大的运输能力。在应激后，它促进Ca2+进入，以换取Na+， Na+之前通过主要的应激诱导途径进入，代表了一种以前未被认识的机制，有助于随后的细胞损伤。当靶向异常Ca2+内流作为营养不良的治疗选择时，需要考虑这种复杂性。
In Duchenne muscular dystrophy, deficiency of the cytoskeletal protein dystrophin leads to well-described defects in skeletal muscle, but also to dilated cardiomyopathy, accounting for about 20% of the mortality. Mechanisms leading to cardiomyocyte cell death and cardiomyopathy are not well understood. One hypothesis suggests that the lack of dystrophin leads to membrane instability during mechanical stress and to activation of Ca2+ entry pathways. Using cardiomyocytes isolated from dystrophic mdx mice we dissected the contribution of various putative Ca2+ influx pathways with pharmacological tools. Cytosolic Ca2+ and Na+ signals as well as uptake of membrane impermeant compounds were monitored with fluorescent indicators using confocal microscopy and photometry. Membrane stress was applied as moderate osmotic challenges while membrane current was quantified using the whole-cell patch-clamp technique. Our findings suggest a major contribution of two primary Ca2+ influx pathways, stretch-activated membrane channels and short-lived microruptures. Furthermore, we found evidence for a secondary Ca2+ influx pathway, the Na+-Ca2+ exchange (NCX), which in cardiac muscle has a large transport capacity. After stress it contributes to Ca2+ entry in exchange for Na+ which had previously entered via primary stress-induced pathways, representing a previously not recognized mechanism contributing to subsequent cellular damage. This complexity needs to be considered when targeting abnormal Ca2+ influx as a treatment option for dystrophy.
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影响因子：
3.8
作者：
Babich, Olga;Matveev, Victor;Harris, Andrew L;Shirokov, Roman
通讯作者：
Shirokov, Roman
NAV1.4营养不良骨骼肌的放松管制导致NA+超负荷并增强细胞死亡。
影响因子：
3.8
作者：
Hirn, Carole;Shapovalov, George;Petermann, Olivier;Roulet, Emmanuelle;Ruegg, Urs T.
通讯作者：
Ruegg, Urs T.
影响因子：
3.4
作者：
LACAMPAGNE, A;GANNIER, F;LEGUENNEC, JY
通讯作者：
LEGUENNEC, JY
影响因子：
2.8
作者：
Quinlan, JG;Hahn, HS;Levin, LS
通讯作者：
Levin, LS
影响因子：
3.4
作者：
Maskarinec, SA;Hannig, J;Lee, KYC
通讯作者：
Lee, KYC