ARC磷酸化是麻醉预处理抗细胞凋亡作用的关键因素  

作　　者：Xiyuan Lu, MS Peter G. Moore, MD, PhD Hong Liu, MD Saul Schaefer, MD 毛祖旻(译) 李士通(校) 

机构地区：[1]Department of Internal Medicine, Division of Cardiovascular Medicine, and ＊Department of Anesthesiology and Pain Medicine, University of California, Davis, Davis, California and ＊Cardiology Section, Department of Veteran Affairs, Northern California Health Care System, Mather, California [2]不详

出　　处：《麻醉与镇痛》2013年第6期31-38,共8页Anesthesia & Analgesia

摘　　要：背景在心肌缺血一再灌注（ischemia／reperfusion，I／R）之前短暂暴露于挥发性麻醉剂中，被称为麻醉预处理，它可限制心肌损伤并抑制凋亡。半胱天冬酶募集域细胞凋亡抑制剂（apoptosisrepressorwithcaspaserecruitmentdomain，ARC）是一种可保护I／Rgf起的心肌凋亡的新型蛋白，可被磷酸化调控。因此我们假设麻醉预处理的抗凋亡作用可tt部分与ARC的磷酸化有关。方法实验中我们采用I／R的大鼠心脏模型进行七氟醚麻醉预处理。除了测定左室功能，也测定了给予和不给予麻醉预处理的ARC磷酸化水平。因为ARC的磷酸化状态是由钙神经素和蛋白激酶CK2所决定，所以通过钙神经素活性以及应用钙神经素抑制剂FK506和ARC磷酸化抑制剂4，5，6，7．四溴苯并三唑（TBB）来测定。结果无麻醉预处理的I／R组钙神经素增加，ARC磷酸化水平降低，而麻醉预处理可显著改善功能恢复、减少缺血损伤、限制钙神经素活性的增加、增加ARC磷酸化水平、减少细胞色素c释放以及阻止I／R后半胱天冬酶-8的增加。麻醉预处理的作用与FK506相似，可被TBB消除。结论本研究证实了一种麻醉预处理预防I／R后钙神经素增加的新途径，通过增加ARC的磷酸化水平减少凋亡标记物。BACKGROUND： Transient exposure to volatile anesthetics before cardiac ischemia/reperfusion （I/R）, termed anesthetic preconditioning, limits myocardial injury and inhibits apoptosis. Apoptosis repressor with caspase recruitment domain （ARC） is a novel protein that has been demonstrated to protect cardiomyocytes from apoptosis induced by I/R and is regulated by phosphorylation. We therefore hypothesized that the antiapoptotic effect of anesthetic preconditioning is, in part, mediated by phosphorylation of ARC. METHODS： In the experiments we used a perfused rat heart model of sevoflurane anesthetic preconditioning and I/R. In addition to measures of left ventricular function, phosphorylation of ARC was measured with and without anesthetic preconditioning. Because the phosphorylation status of ARC is determined by calcineurin and protein kinase CK2, the role of ARC was defined by measuring calcineurin activity and using the calcineurin inhibitor FI（506 and the ARC phosphorytation inhibitor 4, 5, 6, 7-tetrabromobenzotrizole （TBB）. RESULTS： I/R without anesthetic preconditioning increased calcineurin and reduced ARC phosphorylation levels, whereas anesthetic preconditioning significantly improved functional recovery, decreased ischemic injury, limited the increase in calcineurin activity, increased the phosphoryiation level of ARC, reduced cytochrome c release, and blocked the increase in caspase-8 after I/R. The effects of anesthetic preconditioning were mirrored by FK506 and abolished by TBB. CONCLUSION： This study has identified a novel cardiac pathway in which anesthetic preconditioning prevents the increase in calcineurin after I/R, resulting in increased phosphorylated ARC and decreased markers of apoptosis.

关 键 词：挥发性麻醉剂 抗细胞凋亡作用 磷酸化调控 预处理 ARC 钙神经素抑制剂 细胞凋亡抑制剂 蛋白激酶CK2 

分 类 号：R971.2[医药卫生—药品]