Low dose N,N-dimethylsphingosine is cardioprotective and activates cytosolic sphingosine kinase by a PKCε dependent mechanism
Low dose N,N-dimethylsphingosine is cardioprotective and activates cytosolic sphingosine kinase by a PKCε dependent mechanism
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DOI：
10.1016/j.cardiores.2006.06.010
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发表时间：
2006-09-01
影响因子：
10.8
通讯作者：
Karliner, Joel S.
中科院分区：
文献类型：
--
作者：
Jin, Zhu-Qiu;Karliner, Joel S.
目的：N，N-二甲基鞘氨醇(DMS)是鞘氨醇-1-磷酸(SIP)形成的关键酶--鞘氨醇-1-磷酸(SphK)的抑制剂。我们先前的研究表明，SphK对心肌缺血预适应具有心脏保护作用，而SphK在心肌缺血预适应中起关键作用。虽然DMS是一种内源性鞘磷脂，但其在低浓度时对心功能和心脏保护作用的研究尚未见报道。方法：在Langendorff灌流的野生型和蛋白激酶C(PKC)epsilon缺失的小鼠心脏上，测定心功能、梗塞面积和SphK活性。结果：0.3mM和1mU M DMS预处理10min对缺血/再灌注损伤具有保护作用。心功能(LVDP、+/-dp/dtmax)明显改善，心肌梗死面积缩小。在PKC epsilon缺失的小鼠心脏，DMS诱导的心脏保护作用被取消。体外给药1 mU M-DMS可提高胞浆SphK活性。这种增强的SphK活性在PKC epsilon缺失的小鼠心脏中被取消。DMS还增加了PKC epsilon从颗粒到胞浆的移位，但对PKCα的分布没有影响。免疫共沉淀结果表明，SphK1与Ser729上磷酸化的PKC epsilon相互作用。DMS还增加了胞浆Akt磷酸化(Ser473)和Akt从Triton不溶部分到胞浆的易位。结论：DMS具有双相心肌保护作用。较高浓度(10mU M)的DMS具有抑制作用，而低浓度(0.3mM和1mM)的DMS可保护小鼠心脏免受缺血/再灌注损伤。DMS通过PKC epsilon依赖机制激活胞浆中的SphK。PKC-epsilon-SphK-S1P-Akt通路参与DMS诱导的心脏保护作用。(C)2006年欧洲心脏病学会。爱思唯尔出版，版权所有。
Objective: N, N-Dimethylsphingosine (DMS) is recognized as an inhibitor of sphingosine kinase (SphK), a key enzyme responsible for the formation of sphingosine-1-phosphate (SIP). We previously showed that SIP was cardioprotective and that SphK was critical for myocardial ischemic preconditioning. Although DMS is an endogenous sphingolipid, its effect on cardiac function and cardioprotection at low concentration has not been studied.Methods: In Langendorff-perfused wild-type and protein kinase C (PKC)epsilon-null mouse hearts, cardiac function, infarction size, and SphK activity were measured.Results: Pretreatment with 0.3 mu M and 1 mu M DMS for 10 min protected against ischemia/reperfusion injury. Cardiac function (LVDP, +/- dP/dtmax) was improved and infarction size was reduced. The cardiac protection induced by DMS was abolished in PKC epsilon-null mouse hearts. Administration of 1 mu M DMS ex vivo increased cytosolic SphK activity. This enhanced SphK activity was abolished in PKC epsilon-null mouse hearts. DMS also increased PKC epsilon translocation from the particulate to the cytosolic fraction with no effect on PKC alpha distribution. Co-immunoprecipitation showed that SphK1 interacted with PKC epsilon phosphorylated on Ser729. DMS also increased cytosolic Akt phosphorylation (Ser 473) and Akt translocation from a Triton-insoluble fraction to the cytosol.Conclusions: DMS has a biphasic effect on cardioprotection. Higher concentrations (10 mu M) are inhibitory, whereas a low concentration (0.3 mu M and 1 mu M) of DMS protects murine hearts against ischemia/reperfusion injury. DMS activates SphK in the cytosol via a PKC epsilon dependent mechanism. The PKC epsilon-SphK-S1P-Akt pathway is involved in the cardiac protection induced by DMS. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.