Study on cardiac dysfunction caused by abnormal ionic regulation.

离子调节异常引起的心功能障碍研究。

• 批准号: 14370236
• 负责人: SHIGEKAWA Munekazu
• 金额: $ 5.25万
• 依托单位: Senri-Kinran University (2003)National Cardiovascular Center Research Institute (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370236/
• 关键词: Dilated Cardiomyopathy; Muscular Dystrophy; Dystrophin-glycoprotein Complex; Muscle degeneration; Na+; Ca2+ Exchanger; H+ Exchanger; 心不全; 心筋症; ジストロフィー; ストレッチ活性化チャネル; サルコグリカン

Disruption of the dystrophin-glycoprotein complex(DGC) caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. In this study, we observed that the growth factor-regulated cation channel GRC, which belongs to the transient-receptor-potential(TRP) channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or 5-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca^<2+> influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca^<2+>. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca^<2+> overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by DGC disruption. Besides these studies, we explored the regulatory mechanisms of Na^+/Ca^<2+> and Na^+/H^+ exchangers and their roles in the genesis of cardiac dysfunction.

由肌营养不良蛋白或肌聚糖的遗传缺陷引起的肌营养不良蛋白-糖蛋白复合物（DGC）的破坏导致人类和动物模型中的肌营养不良和/或心肌病。然而，导致心肌细胞变性的关键早期分子事件仍然难以捉摸。在这项研究中，我们观察到，生长因子调节的阳离子通道GRC，这属于瞬时受体电位（TRP）通道家族，是升高的骨骼肌和/或心肌肌膜的营养不良的人类患者和动物模型缺乏肌营养不良蛋白或5-肌聚糖。然而，总细胞GRC在正常和营养不良肌肉之间没有显著差异。从δ-肌聚糖缺陷的BIO14.6仓鼠制备的肌管的特性分析显示，GRC响应于肌细胞牵拉而被激活，并且负责增强的Ca^2+内流和由此产生的细胞损伤，这通过肌酸磷酸激酶流出来测量。我们发现细胞牵张增加了GRC向肌膜的移位，这需要外部Ca^<2+>的进入。与这些发现相一致的是，在转基因小鼠模型中，心脏特异性表达的GRC由于Ca^2+超载而产生心肌病，疾病表达与肌膜GRC水平大致平行。结果表明，GRC是由DGC破坏引起的肌细胞变性的发病机制中的关键参与者。除此之外，我们还探讨了Na^+/Ca^<2+>和Na^+/H^+交换体的调节机制及其在心功能不全发生中的作用。

项目成果

Iwata, Y., Katanosaka, Y., Arai, Y., Komamura, K., et al.: "A novel mechanism of myocyte degeneration involving the Ca^<2+>-permeable growth factor-regulated channel."J.Cell.Biol.. 161(5). 957-967 (2003)

Iwata, Y.、Katanosaka, Y.、Arai, Y.、Komamura, K. 等人：“一种涉及 Ca^2-渗透性生长因子调节通道的心肌细胞变性的新机制。”J.Cell

Muraki, K., Iwata, Y., Katanosaka, Y.et al.: "TRV2 is a component of osmotically sensitive cation channels is murine aortic myocytes."Circ.Res.. 93(4). 829-838 (2003)

Muraki, K.、Iwata, Y.、Katanosaka, Y.等人：“TRV2 是鼠主动脉肌细胞渗透敏感阳离子通道的一个组成部分。”Circ.Res.. 93(4)。

Pang, T., Hisamitsu, T., Mori, Shigekawa, M., Wakabayashi, S: "Role of Calcineurin B Homologous Protein in pH Regulation by the Na^+/H^+ Exchanger 1: Tightly Bound Ca^<2+> Ions as Important Structural Elements."Biochemistry. 43. 3628-3636 (2004)

Pang, T.、Hisamitsu, T.、Mori、Shigekawa, M.、Wakabayashi, S：“钙调神经磷酸酶 B 同源蛋白在 Na^ /H^ 交换器 1 的 pH 调节中的作用：紧密结合的 Ca^<2> 离子作为

Iwata, Y., Katanosaka, Y., Arai, Y., Komamura, K.et al.: "A novel mechanism of myocyte degeneration involving the Ca^<2+>-permeable growth factor-regulated channel."J.Cell.Biol.. 161(5). 957-967 (2003)

Iwata, Y.、Katanosaka, Y.、Arai, Y.、Komamura, K.等人：“涉及Ca^2-渗透性生长因子调节通道的心肌细胞变性的新机制。”J.Cell。

Wakabayashi S, Hisamitsu T, Pang T, Shigekawa M: "Mutation of Arg440 and Gly455/Gly456 oppositely change pH-sensing of Na+/H+ exchanger NHE1"Journal of Biological Chemistry. 278(発表予定). (2003)

Wakabayashi S、Hisamitsu T、Pang T、Shigekawa M：“Arg440 和 Gly455/Gly456 的突变相反地改变 Na+/H+ 交换器 NHE1 的 pH 感应”《生物化学杂志》278（待出版）。