Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, South Dakota, USA.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, California, USA.
FASEB J. 2018 Oct;32(10):5426-5435. doi: 10.1096/fj.201800231R. Epub 2018 Apr 26.
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)-mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P knockout (TS1PKO) mice generated by crossing S1pr mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1PKO mice exhibited sustained deficiency of both CD4 and CD8 T cells in the blood. The TS1PKO 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, TS1PKO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P 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.
T 细胞浸润与糖尿病患者发生心脏病的风险增加有关。T 细胞鞘氨醇 1-磷酸受体 1（S1P）介导的信号转导指导 T 淋巴细胞的迁移。T 细胞 S1P 激活对糖尿病小鼠模型中心脏纤维化的影响仍有待探讨。为此，通过将 S1pr 小鼠与 Lck-Cre 小鼠杂交生成条件性 T 细胞 S1P 敲除（TS1PKO）小鼠，用于链脲佐菌素诱导的糖尿病心肌病模型。TS1PKO 小鼠在血液中持续缺乏 CD4 和 CD8 T 细胞。TS1PKO 载体对照小鼠心脏表现出改变的表型，其特征是在正常葡萄糖水平下心肌纤维化增加和心脏收缩力降低。与同窝对照糖尿病小鼠相比，TS1PKO 糖尿病小鼠在糖尿病诱导 11 周后心脏功能改善，心脏纤维化减轻。我们的结果表明，T 细胞 S1P 信号激活在心脏纤维化的发病机制方面与葡萄糖水平具有双重作用：T 细胞 S1P 激活在正常血糖水平下发挥抗纤维化作用，但在高血糖下会加重纤维化。-Abdullah，CS，Jin，Z-Q。靶向敲除 T 细胞 S1P 受体 1 可改善链脲佐菌素诱导的糖尿病小鼠的心脏纤维化。
