EFFECTS OF NEUROENDOCRINE FACTORS ON CARDIAC NA^+/CA^<2+> EXCHANGER

神经内分泌因素对心脏NA^/CA^<2>交换器的影响

• 批准号: 13670092
• 负责人: KIMURA Junko
• 金额: $ 1.98万
• 依托单位: FUKUSHIMA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670092/
• 关键词: Na-Ca EXCHANGE; CARDIAC MYOCYTES; WHOLE-CELL CLAMP; ACIDOSIS; PRECONDITIONING; REACTIVE OXYGEN; SMALL G-PROTEIN; mRNA; Na-Ca交換; 心筋; パッチクランプ; モルモット; 膜輸送; ナトリウム; カルシウム; フリーラジカル; sodium-calcium exchange; cardiac myocytes; whole cell clamp /

Various neuroendocrine factors are known to be involved in heart failure.We tested the effects of isoproterenol, phanylephrine, angiotensine II and endotheline on Na^+/Ca^<2+> exchange (NCX) current but did not see any change in the current. Therefore we investigated not the membrane receptors but intracellular signaling pathways using guinea pig cardiac ventricular cells and H9c2 cells derived from rat cardiac myocytes. Combining the methods of the whole-cell voltage clamp, RT-PCR and the Western blot, the following themes were investigated.(1)Effects of acidic preconditioning on NCX.(2)Mechanism of activation of NCX by Reactive oxygen species.(3)Signaling pathways of modulation of NCX mRNA and protein.We obtained the following results. (1)Acidic preconditioning decreases NCX-NHE interaction via activation of PKCc and inhibits Ca^<2+> overload. (2)Two different pathways exist for activation of NCX by hydrogen peroxide. One is indirectly via activation of NHE. Another is via direct tyrosine phosphorylation of NCX by activating MEK. (3) A small G-protein Rho is involved in modulation of NCX mRNA expression. We will further pursue the projects to fully elucidate the mechanisms.

已知各种神经内分泌因子与心力衰竭有关。我们测试了异丙肾上腺素，苯肾上腺素，血管紧张素II和内皮素对Na^+/Ca^<2+> Exchange（NCX）电流的影响，但目前没有任何变化。因此，我们不是研究了膜受体，而是使用豚鼠心室细胞和源自大鼠心肌细胞的H9C2细胞的细胞内信号通路。结合了整个细胞电压夹，RT-PCR和Western印迹的方法，研究了以下主题。（1）酸性预处理对NCX的影响（2）反应性氧物种激活NCX的机制。（3个）（3）（3 ）NCX mRNA和蛋白质调节的信号通路。我们获得了以下结果。 （1）酸性预处理通过激活PKCC降低NCX-NHE相互作用，并抑制CA^<2+>过载。 （2）存在两种不同的途径，用于通过过氧化氢激活NCX。一个通过激活NHE间接。另一种是通过激活MEK的直接酪氨酸磷酸化。 （3）一个小的G蛋白RHO参与NCX mRNA表达的调节。我们将进一步追求这些项目以充分阐明机制。

项目成果

Watanabe Y, Kimura J.: "Blocking effect of bepridil on Na^+/Ca^<2+> exchange current in guinea pig cardiac ventricular myocytes"Japanese Journal of Pharmacology. 85. 370-375 (2001)

Watanabe Y，Kimura J.：“苯普地尔对豚鼠心室肌​​细胞中Na ^ /Ca ^ 2 交换电流的阻断作用”日本药理学杂志。

Hinata M, Yamamura H, Li L, Watanabe Y, Watano T, Imaizumi Y, Kimura J: "Re-examination of the stoichiometry of Na^+/Ca^<2+> exchange with whole-cell voltage clamp of guinea-pig ventricular myocytes"Annals of New York Academy of Sciences. (in press). (200

Hinata M、Yamamura H、Li L、Watanabe Y、Watano T、Imaizumi Y、Kimura J：“用豚鼠心室肌​​细胞的全细胞电压钳重新检查 Na^ /Ca^<2 > 交换的化学计量

Yokoyama K, Ishibashi T, Ohwarara H, Kimura J, Matsuoka I, Sakamoto T, Nagata K, sugimoto K, sakurada S Maruyama Y.: "HMG-CoA reductase inhibitors suppress intracellular calcium mobilization and membrane current induced by lysophosphatidylcholine in endot

Yokoyama K、Ishibashi T、Ohwarara H、Kimura J、Matsuoka I、Sakamoto T、Nagata K、sugimoto K、sakurada S Maruyama Y.：“HMG-CoA 还原酶抑制剂抑制内点中溶血磷脂酰胆碱诱导的细胞内钙动员和膜电流

Li L, Kimura J.: "Effect of KB-R7943 on oscillatory Na^+/Ca^<2+> exchange current in guinea pig ventricular myocytes"Ann N Y Adac Sci. 976. 539-542 (2002)

Li L，Kimura J.：“KB-R7943对豚鼠心室肌​​细胞振荡Na^/Ca^2>交换电流的影响”Ann N Y Adac Sci。

Li L, Matsuoka I, Suzuki Y, Watanabe Y, Ishibashi T, Yokoyama K, Maruyama Y, Kimura J: "Inhibitory effect of fluvastatin on lisophosphatidylcholine-induced non-selective cation current in guinea pig ventricular myocytes"Mol Pharmacol. 62. 602-607 (2002)

Li L、Matsuoka I、Suzuki Y、Watanabe Y、Ishibashi T、Yokoyama K、Maruyama Y、Kimura J：“氟伐他汀对豚鼠心室肌​​细胞中赖索磷脂酰胆碱诱导的非选择性阳离子电流的抑制作用”Mol Pharmacol。