Redox Regulation of Signal Transduction Mechanism in the Heart

心脏信号转导机制的氧化还原调节

• 批准号: 13470483
• 负责人: KUROSE Hitoshi
• 金额: $ 9.28万
• 依托单位: Kyushu University (2002)The University of Tokyo (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/en/grant/KAKENHI-PROJECT-13470483/
• 关键词: reactive oxygen species; oxidative stress; cysteine residue; G protein; signaling molecule; intracellular mediator; 酸素毒性; 細胞保護; セリン変異体

Reactive oxygen species (ROS) has been considered as an 'evil player' due to a strong reactivity. We have reported that trimeric G protein (G_i/G_0) is directly activated by one of ROS hydrogen peroxide (H_2O_2) in rat neonatal myocytes. Upon activation of G_i/G_0 by H_2O_2, Gβγis released from trimeric G_i/G_0 and the released Gβγ activates ERK to protect the cells against oxidative damage. We have now identified the amino acids that are modified by H_2O_2, and have found that the H_2O_2-mediated modification of cysteine residues located at 287 and 326 is necessary for activation of G_i. These results indicate that ROS can work as an intracellular mediator in the heart, and suggest that ROS generated by receptor stimulation can activate G_i and G_0. Other than the treatment of cells with H_2O_2, ROS was generated by receptor stimulation. Although angiotensin II stimulation generated ROS and induced MAP kinase activation, angiotensin II stimulation could not activate G_i and G_0. Therefore, we concluded that the amount of ROS is an important factor for activation of G protein. We have also found that the expression of peroxiredoxin II (PrxII) eliminates ROS from cells, and PrxII abolishes c-Jun NH_2-terminal kinase (JNK) activation without affecting ERK and p38 MAPK activation. It is concluded that angiotensin II activates specific signaling pathway leading to JNK activation. It also suggests that ROS can work as an intracellular mediator.

由于反应性强，活性氧（ROS）被认为是“邪恶的玩家”。我们已经报道说，三聚合物G蛋白（G_I/G_0）在大鼠新生儿心肌细胞中直接被一种ROS氢（H_2O_2）直接激活。 H_2O_2激活G_I/G_0后，从三聚体G_I/G_0释放的GβγIS和释放的Gβγ激活ERK，以保护细胞免受氧化损伤。现在，我们已经确定了由H_2O_2修饰的氨基酸，并发现位于287和326的半胱氨酸残留物的H_2O_2介导的修饰对于激活G_I是必需的。这些结果表明ROS可以作为心脏中的细胞内介体工作，并表明受体刺激产生的ROS可以激活G_I和G_0。除了用H_2O_2处理细胞外，通过受体刺激产生ROS。尽管血管紧张素II刺激产生了ROS并诱导MAP激酶激活，但血管紧张素II刺激无法激活G_I和G_0。因此，我们得出的结论是，ROS的量是激活G蛋白的重要因素。我们还发现，过氧蛋白II（PRXII）的表达消除了细胞中的ROS，而PRXII废除了C-JUN NH_2-末端激酶（JNK）激活而不会影响ERK和p38 MAPK激活。结论是，血管紧张素II激活了导致JNK激活的特定信号传导途径。这也表明ROS可以用作细胞内介体。

项目成果

Endo, A. et al.: "Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII"J. Biol. Chem.. 277. 23747-23754 (2002)

Endo, A. 等人：“1-磷酸鞘氨醇通过血管内皮生长因子受体和 CrkII 诱导细胞膜褶皱并增加人脐静脉内皮细胞的运动性”J.

Shiia, T., Nagao T. and Kurose H.: "Low affinity of β_i-adrenergic receptor for β-arrestins explains the resistance to agonist-induced internalization"Life Sci.. 68. 2251-2257 (2001)

Shiia, T.、Nagao T. 和 Kurose H.：“β_i-肾上腺素能受体对 β-arrestins 的低亲和力解释了对激动剂诱导内化的抵抗”Life Sci.. 68. 2251-2257 (2001)

Isogaya, M. et al.: "Enhanced cAMP response of the naturally occurring mutant of human β_3-adrenoceptor"Jpn. J. Pharmacol.. 88. 314-318 (2002)

Isogaya，M.等人：“人β_3-肾上腺素受体天然突变的增强的cAMP反应”Jpn. J. Pharmacol.. 88. 314-318 (2002)

Arai K., Maruyama Y., Nishida Tanabe S., Takagahara S., Turner J. H., Kozasa T., Mori Y., Nagao T., and Kurose H.: "Differential requirement of Gα_<12>, Gα_<13>, Gα_q and Gβγ for endothelin-1-induced JNK and ERK activation"Mol. Pharmacol.. 63. 478-488 (20

Arai K.、Maruyama Y.、Nishida Tanabe S.、Takagahara S.、Turner J. H.、Kozasa T.、Mori Y.、Nagao T. 和 Kurose H.：“Gα_<12>、Gα_<13> 的差异要求、Gα_q 和 Gβγ 对于内皮素-1 诱导的 JNK 和 ERK 激活“Mol. Pharmacol.. 63. 478-488 (20

Endo A., Nagashima K., Kurose H., Mochizuki S., Matsuda M., and Mochizuki N.: "Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII."J.

Endo A.、Nagashima K.、Kurose H.、Mochizuki S.、Matsuda M. 和 Mochizuki N.：“1-磷酸鞘氨醇通过血管内皮生长因子受体和 CrkII 诱导细胞膜褶皱并增加人脐静脉内皮细胞的运动性