S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species
S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species
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DOI：
10.1093/cvr/cvp312
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发表时间：
2010-02-01
影响因子：
10.8
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
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作者：
Takuwa, Noriko;Ohkura, Sei-Ichiro;Takuwa, Yoh
目的鞘氨醇激酶1 （SPHK1）及其产物鞘氨醇-1-磷酸（S1P）和S1P受体亚型在缺血预处理和心脏缺血/再灌注损伤动物模型中对心肌细胞具有保护作用。为了更深入地了解SPHK1在体内的作用，我们产生了SPHK1转基因（TG）小鼠并分析了心脏表型。方法与结果SPHK1- tg小鼠在多种组织中过表达SPHK1，酶活性增加近20倍。TG小鼠生长正常，血液化学、细胞计数、心率和血压正常。出乎意料的是，SPHK1高而非低表达的TG小鼠出现了进行性心肌变性和纤维化，胚胎基因上调，RhoA和Rac1活性升高，Smad3磷酸化受到刺激，氧化应激标志物水平升高。用pitavastatin（一种已建立的Rho家族G蛋白抑制剂）治疗幼年TG小鼠，或删除S1P（一种主要的心肌S1P受体亚型，与Rho GTPases偶联并激活Smad信号传导），均可抑制心脏纤维化，同时抑制sphk1依赖性Smad-3磷酸化。此外，抗氧化剂n -2-巯基丙基甘氨酸可以减少活性氧（ROS），也可以抑制心脏纤维化。在体内缺血/再灌注损伤中，SPHK1-TG小鼠心肌梗死面积比野生型小鼠减少30%。这些结果表明，SPHK1-S1P信号的慢性激活既可以通过S1P介导的ROS进行病理性心脏重构(3)，也可以起到良好的心脏保护作用。
Aims Sphingosine kinase 1 (SPHK1), its product sphingosine-1-phosphate (S1P), and S1P receptor subtypes have been suggested to play protective roles for cardiomyocytes in animal models of ischaemic preconditioning and cardiac ischaemia/reperfusion injury. To get more insight into roles for SPHK1 in vivo, we have generated SPHK1-transgenic (TG) mice and analysed the cardiac phenotype.Methods and results SPHK1-TG mice overexpressed SPHK1 in diverse tissues, with a nearly 20-fold increase in enzymatic activity. The TG mice grew normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Unexpectedly, TG mice with high but not low expression levels of SPHK1 developed progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile TG mice with pitavastatin, an established inhibitor of the Rho family G proteins, or deletion of S1P(3), a major myocardial S1P receptor subtype that couples to Rho GTPases and transactivates Smad signalling, both inhibited cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, which reduces reactive oxygen species (ROS), also inhibited cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct was 30% decreased in SPHK1-TG mice compared with wild-type mice.Conclusion These results suggest that chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through ROS mediated by S1P(3) and favourable cardioprotective effects.