The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction.
The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction.
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DOI：
10.1038/s41598-017-07573-2
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发表时间：
2017-08-10
影响因子：
4.6
通讯作者：
Kurose H
中科院分区：
文献类型：
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作者：
Nagasaka A;Mogi C;Ono H;Nishi T;Horii Y;Ohba Y;Sato K;Nakaya M;Okajima F;Kurose H
心肌梗死（MI）是由冠状动脉阻塞引起的缺血性心脏病。MI后，无氧糖酵解产生的乳酸增加，浸润的免疫细胞产生严重的炎症，导致缺血性心脏酸中毒。然而，这种pH值降低的生理意义在很大程度上仍然未知。T细胞死亡相关基因8（TDAG 8）是在心脏巨噬细胞上发现的质子感应G蛋白偶联受体，其识别细胞外质子的增加。我们证明了TDAG 8负调控趋化因子Ccl 20的转录。TDAG 8 KO小鼠的梗死心脏显示CCL 20表达和表达CCL 20受体CCR 6的浸润性IL-17 A产生γδT细胞的数量增加。因此，在MI操作的TDAG 8 KO小鼠中观察到与MI后功能恶化相关的过量IL-17 A产生。与野生型小鼠相比，TDAG 8 KO小鼠MI后存活率和心功能显著降低。因此，我们的研究结果表明，TDAG 8是MI的关键调节因子和潜在的治疗靶点。
Myocardial infarction (MI) is an ischaemic heart condition caused by the occlusion of coronary arteries. Following MI, lactic acid from anaerobic glycolysis increases and infiltrating immune cells produce severe inflammation, which leads to acidosis in the ischaemic heart. However, the physiological implication of this pH reduction remains largely unknown. T-cell death-associated gene 8 (TDAG8) is a proton-sensing G protein-coupled receptor found on cardiac macrophages that recognise increases in extracellular protons. We demonstrated that TDAG8 negatively regulates the transcription of the chemokine Ccl20. The infarcted hearts of TDAG8 KO mice showed an increase in CCL20 expression and the number of infiltrating IL-17A-producing γδT cells that express CCR6, a receptor for CCL20. Accordingly, excessive IL-17A production, which is linked to the functional deterioration after MI, was observed in MI-operated TDAG8 KO mice. The survival rate and cardiac function significantly decreased in TDAG8 KO mice compared with those in wild-type mice after MI. Thus, our results suggest that TDAG8 is a key regulator of MI and a potential therapeutic target.