Novel mechanism on the ischemic preconditioning : Role of AMP deaminase family for adenosine production

缺血预处理的新机制：AMP 脱氨酶家族在腺苷生产中的作用

• 批准号: 11670680
• 负责人: HISATOME Ichiro
• 金额: $ 1.92万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670680/
• 关键词: AMP deaminase; Ischemic preconditioning; myosin heary chain; human heat; AMP deaminase、; AMP deaminase family; ミオシン重鎖

Adenosine is known to be the mediator to facilitate the ischemic preconditioning of the heart. Adenosine is converted from extracellular AMP by ecto 5'-nucleotidase, and is also produced from intracellular adenosine monophosphate (AMP) by cytosolic 5'-nucleotidase, suggesting adenosine concentration will be influenced by intracellular AMP concentration. AMP concentration can be degradated not only by cytosolic 5'-nucleotidase into adenosine but also by AMP deaminase into inosine monophosphate (IMP). Therefore, adenosine concentration would be decreased by the activation of AMP deaminase. AMP deaminase family is composed of muscular AMPD1, hepatic AMPD2 and blood type AMPD3. However the distribution and function of cardiac AMP deaminase is not still characterized. In the present study, we studied the localization and the function of cardiac AMP deaminase. While the right atrium expressed the message and the protein of AMPD1, 2, and 3, the left atrium and both ventricles expressed AMPD2 … More and 3 in patients with heart failure. AMPD1 has the myosin heavy chain binding site which included the consensus sequence of PVEK.Based on the alignment for the amino acid sequence, AMPD2 and 3 possess the myosin binding site as well. The heterologous expression study of both AMP deaminase family and myosin heavy chain showed that AMPD3 can bind the myosin heavy chain as AMPD1, but AMPD2 did not bind to myosin heavy chain. While the activity of myosin heavy chain-bound AMPD1 was significantly higher than that of unbound AMPD1, the activity of AMPD3 did not alter under either myosin heavy chain bound or unbound condition. Under ischemic condition of the heart myosin bound AMP deaminase activity (AMPD3 dominantly expressed) did not change, although under ischemic condition of the skeletal muscle myosin bound AMP deaminase activity (dominantly AMPD1 expressed) significantly elevated. In addition AMPD 3 can bind to ecto 5'- nucleotidase, as AMPD1 and 2 can bind to it. These results suggest that cardiac ischemia facilitated myosin heavy chain to bind to AMPD3 in order to both ecto and cytosolic 5'-nucleotidase can utilize the AMP to convert into adenosine, which would lead to activate the ischemic preconditioning of the heart. Less

已知腺苷是促进心脏缺血性预处理的介体。腺苷通过ECTO 5'-核苷酸酶从细胞外AMP转化，也是细胞内腺苷单磷酸（AMP）通过胞质5'-核苷酸酶产生的，这表明腺苷浓度将受细胞内AMP浓度的影响。 AMP浓度不仅可以通过胞质5'-核苷酸酶降解为腺苷，而且还可以通过AMP脱氨酶转化为单磷酸（IMP）。因此，通过AMP脱氨酶的激活将改善腺苷浓度。 AMP脱氨酶家族由肌肉AMP1，肝AMP2和血型AMP3组成。然而，心脏AMP脱氨酶的分布和功能仍未表征。在本研究中，我们研究了心脏AMP脱氨酶的定位和功能。右心房表达了AMPD1、2和3的蛋白质，而心力衰竭患者的左心房和两个心室表达了AMPD2…更多，3个。 AMPD1具有肌球蛋白重链结合位点，其中包括PVEK的共有序列。基于氨基酸序列的比对，AMPD2和3也具有肌球蛋白结合位点。 AMP脱氨酶家族和肌球蛋白重链的异源表达研究表明，AMPD3可以将肌球蛋白重链作为AMPD1结合，但是AMPD2没有与肌球蛋白重链结合。尽管肌球蛋白重结合AMP结合AMP结合AMP结合的AMP结合AMP结合的AMP结合活性（AMPD3显着表达）并没有改变，尽管在骨骼肌肌球蛋白结合的骨骼肌肌球蛋白结合的AMP Deaminase活性（显着表达的AMPD1）显着升高。另外，AMPD 3可以与Ecto 5'-核苷酸酶结合，因为AMPD1和2可以与之结合。这些结果表明，制备肌球蛋白重链以与AMPD3结合的心脏缺血，以与Ecto和胞质5'-核苷酸酶均可使用AMP转化为腺苷，从而激活心脏的缺血性预处理。较少的

项目成果

Akira Ohtahara, Ichiro Hisatome, Yasutaka Yamamoto, et al: "The release of the substrate fo xanthine oxidase in hypertensive patients was suppressed by ACE inhibitor and alpha-1 blocker."Journal of Hypertension. (Accepted). (2001)

Akira Ohtahara、Ichiro Hisatome、Yasutaka Yamamoto 等人：“高血压患者中底物黄嘌呤氧化酶的释放受到 ACE 抑制剂和 α-1 阻滞剂的抑制。”高血压杂志。

Tsuboi M, Hisatome I, Morisaki T, et al.: "Mitochondrial DNA deletion associated with the reduction of adenine nucleotides of human atrium and atrial fibrillation"European Journal of Clinical Investigation.. (Accepted). (2001)

Tsuboi M、Hisatome I、Morisaki T 等人：“与人心房腺嘌呤核苷酸减少和心房颤动相关的线粒体 DNA 缺失”《欧洲临床研究杂志》（已接受）。

Kinugawa T,Ogino K,Hlsatome I, et al.: "Altered purine nucleotide degradation in patietns with essential hypertension."Metabolism. (in press).. (2001)

Kinukawa T、Ogino K、Hlsatome I 等人：“改变了原发性高血压患者的嘌呤核苷酸降解。”代谢。

A.Ohtabara,I.Hisatome,Y.Yamamoto, et al.: "The release of the substrate to xanthine oxidase in hypertensive patients was suppressed by ACE inhibitor and alpha-1 blocker."Journal of Hypertension. (in press).. (2001)

A.Ohtabara、I.Hisatome、Y.Yamamoto 等人：“高血压患者中黄嘌呤氧化酶底物的释放受到 ACE 抑制剂和 α-1 阻滞剂的抑制。”高血压杂志。

Ogino K, Kinugawa T, Hisatome I, et al.: "Ammonia response to constant exercise : differences to the lactate respones."Clinical and Experimental Pharmacology and Physiology. 27. 612-617 (2000)

Ogino K、Kinukawa T、Hisatome I 等人：“氨对持续运动的反应：与乳酸反应的差异。”临床和实验药理学和生理学。