Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
J Cell Mol Med. 2021 Mar;25(6):2931-2943. doi: 10.1111/jcmm.16328. Epub 2021 Feb 1.
Increased adenosine helps limit infarct size in ischaemia/reperfusion-injured hearts. In cardiomyocytes, 90% of adenosine is catalysed by adenosine kinase (ADK) and ADK inhibition leads to higher concentrations of both intracellular adenosine and extracellular adenosine. However, the role of ADK inhibition in myocardial ischaemia/reperfusion (I/R) injury remains less obvious. We explored the role of ADK inhibition in myocardial I/R injury using mouse left anterior ligation model. To inhibit ADK, the inhibitor ABT-702 was intraperitoneally injected or AAV9 (adeno-associated virus)-ADK-shRNA was introduced via tail vein injection. H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to elucidate the underlying mechanisms. ADK was transiently increased after myocardial I/R injury. Pharmacological or genetic ADK inhibition reduced infarct size, improved cardiac function and prevented cell apoptosis and necroptosis in I/R-injured mouse hearts. In vitro, ADK inhibition also prevented cell apoptosis and cell necroptosis in H/R-treated H9c2 cells. Cleaved caspase-9, cleaved caspase-8, cleaved caspase-3, MLKL and the phosphorylation of MLKL and CaMKII were decreased by ADK inhibition in reperfusion-injured cardiomyocytes. X-linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.
腺苷的增加有助于限制缺血/再灌注损伤心脏的梗死面积。在心肌细胞中，90%的腺苷由腺苷激酶 (ADK) 催化，ADK 抑制导致细胞内和细胞外腺苷浓度升高。然而，ADK 抑制在心肌缺血/再灌注 (I/R) 损伤中的作用尚不明确。我们使用小鼠左前结扎模型探讨了 ADK 抑制在心肌 I/R 损伤中的作用。为了抑制 ADK，我们通过腹腔内注射抑制剂 ABT-702 或尾静脉注射 AAV9（腺相关病毒）-ADK-shRNA 来实现。我们将 H9c2 细胞暴露于缺氧/复氧 (H/R) 中以阐明潜在机制。心肌 I/R 损伤后 ADK 短暂增加。药理或遗传 ADK 抑制可减少梗死面积，改善心脏功能，并防止 I/R 损伤小鼠心脏中的细胞凋亡和坏死性凋亡。在体外，ADK 抑制还可防止 H/R 处理的 H9c2 细胞中的细胞凋亡和细胞坏死性凋亡。在再灌注损伤的心肌细胞中，ADK 抑制降低了裂解的 caspase-9、裂解的 caspase-8、裂解的 caspase-3、MLKL 以及 MLKL 和 CaMKII 的磷酸化。凋亡抑制蛋白 X 连锁 (XIAP) 通过腺苷受体 A2B 和 A1/Akt 途径磷酸化和稳定，在 ADK 抑制对细胞凋亡和坏死性凋亡的作用中应发挥核心作用。这些数据表明，ADK 通过调节细胞凋亡和坏死性凋亡在心肌 I/R 损伤中发挥重要作用。
