Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice
Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice
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DOI：
10.1096/fj.201800231r
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发表时间：
2018-10-01
期刊：
影响因子：
4.8
通讯作者：
Jin, Zhu-Qiu
中科院分区：
文献类型：
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作者：
Abdullah, Chowdhury S.;Jin, Zhu-Qiu
T细胞的浸润与糖尿病患者心脏病发作的风险增加有关。t细胞鞘氨醇1-磷酸受体1 （S1P(1)）介导的信号传导指导t淋巴细胞运输。t细胞S1P(1)激活对小鼠糖尿病模型心脏纤维化的影响尚待探讨。为此，将S1pr(1)（loxP/loxP）小鼠与Lck-Cre小鼠杂交产生的条件t细胞S1P(1)敲除（TS1P(1)KO）小鼠用于链脲霉素诱导的糖尿病心肌病模型。TS1P(1)KO小鼠表现出血液中CD4（+）和CD8(+) T细胞的持续缺乏。在正常葡萄糖水平下，TS1P(1)KO对照小鼠心脏表现出表型改变，其特征是心肌纤维化增加和心脏收缩力降低。与同窝糖尿病小鼠相比，TS1P(1)KO糖尿病小鼠在糖尿病诱导11周后心功能改善，心肌纤维化减轻。我们的研究结果表明，就葡萄糖水平而言，t细胞S1P(1)信号激活在心脏纤维化的发病机制中起双重作用：t细胞S1P(1)激活在正常血糖状态下具有抗纤维化作用，但在高血糖状态下加剧纤维化。阿卜杜拉，c.s.，金志强。t细胞S1P受体1靶向缺失改善链脲佐菌素诱导的糖尿病小鼠心脏纤维化
Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P(1))-mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P(1) activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P(1) knockout (TS1P(1)KO) mice generated by crossing S1pr(1)(loxP/loxP) mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1P(1)KO mice exhibited sustained deficiency of both CD4(+) and CD8(+) T cells in the blood. The TS1P(1)KO vehicle control mouse hearts featured an altered phenotype characterized by increased myocardial fibrosis and reduced cardiac contractility under normal levels of glucose. Compared with littermate diabetic mice, TS1P(1)KO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P(1) signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P(1) activation exerts antifibrotic effects in normoglycemia but exacerbates fibrosis under hyperglycemia.Abdullah, C. S., Jin, Z.-Q. Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice.