Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 25, Issue 6, Pages 2931-2943Publisher
WILEY
DOI: 10.1111/jcmm.16328
Keywords
adenosine kinase; apoptosis; myocardial ischaemia/reperfusion injury; necroptosis; X-linked inhibitor of apoptosis protein
Categories
Funding
- National Key R&D Program of China [2017YFC0908700, 2017YFC0908703]
- National Natural Science Foundation of China [82072141, 81901934, 81772036, 81701954, 81873950, 81400209]
- National S&T Fundamental Resources Investigation Project [2018FY100600, 2018FY100602]
- Taishan Pandeng Scholar Program of Shandong Province [tspd20181220]
- Key R&D Program of Shandong Province [2019GSF108261, 2018GSF118003, 2017GSF218040]
- Shandong Medical and Health Science Technology Development Plan Project [2018WS329]
- Clinical Research Center of Shandong University [2020SDUCRCC014]
- Science Foundation of Qilu Hospital of Shandong University [2015QLQN13]
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Inhibition of ADK can reduce infarct size, improve cardiac function, and prevent cell apoptosis and necroptosis in myocardial I/R injury. XIAP, phosphorylated and stabilized via adenosine receptors, plays a central role in the effects of ADK inhibition on cell apoptosis and necroptosis.
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.
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