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首页> 外文期刊>Journal of biochemical and molecular toxicology >Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine 1-phosphate.
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Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine 1-phosphate.

机译：鞘氨醇可以使心脏发生变化，并且可以利用与1-磷酸鞘氨醇不同的机制。

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摘要

Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a 75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.
机译：与以前的报道一致，高浓度（5 microM）的鞘氨醇具有心脏毒性，这是通过离体大鼠心脏对缺血/再灌注的反应中梗塞面积的增加而证明的。 5 microM的1-磷酸鞘氨醇（S1P）具有心脏保护作用。但是，在生理浓度（0.4 microM）下，鞘氨醇和S1P在缺血40分钟之前进行灌注（预处理）或在缺血后（再适应）添加至再灌注介质时均可有效保护心脏免受缺血/再灌注损伤。预处理前后，鞘氨醇和S1P的保护作用可通过在再灌注期间左心室发达压力恢复> 75％以及将梗死面积从危险区域的45％降低到8％以下来证明。将S1P（1和3）G蛋白偶联受体拮抗剂VPC23019与S1P一起添加到预处理或后处理培养基中时，它完全阻断了S1P诱导的保护。但是，VPC 23019不会影响0.4 microM鞘氨醇对心脏进行预处理或后处理的能力。预处理的研究表明，用GF109203X抑制蛋白激酶C可阻止S1P进行预处理。但是，GF109203X不会影响0.4 microM鞘氨醇的预处理。同样，与PI3激酶抑制剂渥曼青霉素的共同治疗可阻止S1P（但不是鞘氨醇）的预处理。相比之下，用KT5823抑制蛋白激酶G对S1P预处理没有影响，但是通过鞘氨醇完全消除了预处理。此外，蛋白激酶A抑制肽14-22酰胺可阻断鞘氨醇的预处理，但不能阻断S1P。这些数据首次揭示了鞘氨醇在生理浓度下无毒，而是一种有效的心脏保护剂，其利用的机制与S1P完全不同。一种独立于G蛋白偶联受体，并利用环状核苷酸依赖性途径。

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