FTY720 postconditions isolated perfused heart by a mechanism independent of sphingosine kinase 2 and different from S1P or ischemic postconditioning.
FTY720 postconditions isolated perfused heart by a mechanism independent of sphingosine kinase 2 and different from S1P or ischemic postconditioning.
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DOI：
10.12659/msmbr.883877
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发表时间：
2013-04-09
影响因子：
2.8
通讯作者：
Karliner JS
中科院分区：
文献类型：
--
作者：
Vessey DA;Li L;Imhof I;Honbo N;Karliner JS
我们研究了FTY 720（FTY）在离体灌流小鼠心脏后处理是独立的鞘氨醇1-磷酸（S1 P）途径的假设。离体心脏暴露于缺血或FTY 720的后处理（POST）。通过左心室发展压（LVDP）和梗死面积的恢复来衡量对缺血/再灌注（IR）损伤的保护作用。FTY有效后处理（POST）离体心脏对抗缺血/再灌注（IR）损伤，通过LVDP恢复和低梗死面积测量。FTY的保护作用与S1 P不同，但与鞘氨醇（Sph）相似，对S1 P G蛋白偶联受体（GPCR）的抑制或PI 3激酶的抑制不敏感。然而，FTY和Sph的保护作用被PKA和PKG的抑制剂阻断。因此，FTY遵循与Sph相同的心脏保护途径。这进一步得到了FTY POST在缺乏SphK 2形式的Sph激酶的敲除（KO）小鼠中的研究的支持，SphK 2形式的Sph激酶是FTY磷酸化为S1 P类似物所需的。在没有SphK 2的情况下，FTY（和Sph）POST仍然具有心脏保护作用。这与SphK 2 KO对缺血性POST（IPOST）保护的作用不同。IPOST在KO心脏中无效。为了了解KO心脏中GPCR信号通路是否正常，我们观察了GPCR激动剂S1 P和腺苷的POST。即使在KO心脏中，两者也提供了有效的保护，这表明KO心脏中IPOST的问题是IPOST期间可用于释放的S1 P水平低。因此，与腺苷和S1 P一样，使用FTY或Sph的药理学POST在KO中不受影响。体内给药的FTY 720可能具有双重作用，表现出S1 P样作用和鞘氨醇样作用。似乎后者可能被忽视了，可能在衰老的心脏中更重要。
We investigated the hypothesis that postconditioning by FTY720 (FTY) in isolated perfused mouse hearts is independent of the sphingosine 1-phosphate (S1P) pathway. Ex vivo hearts were exposed to postconditioning (POST) by either ischemia or FTY720. Protection against ischemia/reperfusion (IR) injury was measured by recovery of left ventricular developed pressure (LVDP) and infarct size. FTY effectively postconditioned (POST) ex vivo hearts against ischemia/reperfusion (IR) injury as measured by recovery of LVDP and a low infarct size. FTY protection, unlike S1P but like sphingosine (Sph), was insensitive to inhibition of S1P G-Protein Coupled Receptors (GPCRs) or inhibition of PI3 kinase. Protection by FTY and Sph was however blocked by inhibitors of PKA and PKG. Thus, FTY follows the same cardioprotective pathway as Sph. This was further supported by studies of FTY POST in knockout (KO) mice lacking the SphK2 form of Sph kinase that is needed for phosphorylation of FTY to an S1P analog. In the absence of SphK2, FTY (and Sph) POST was still cardioprotective. This differed from the effect of SphK2 KO on protection by ischemic POST (IPOST). IPOST was not effective in KO hearts. To see if the GPCR signaling pathway to protection is normal in KO hearts, we looked at POST by GPCR agonists S1P and adenosine. Both provided effective protection even in KO hearts suggesting that the problem with IPOST in KO hearts is a low level of S1P available for release during IPOST. Thus, pharmacologic POST with FTY or Sph, like adenosine and S1P, is unaffected in the KO. FTY720 administered in vivo might behave in a dual manner showing both S1P-like effects and sphingosine-like effects. It appears that the latter may have been overlooked and may be the more important in aging hearts.