The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.
The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.
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DOI：
10.1097/fjc.0000000000000031
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发表时间：
2014-02
影响因子：
3
通讯作者：
Raffai RL
中科院分区：
文献类型：
--
作者：
Wang G;Kim RY;Imhof I;Honbo N;Luk FS;Li K;Kumar N;Zhu BQ;Eberlé D;Ching D;Karliner JS;Raffai RL
FTY 720是鞘氨醇-1-磷酸的类似物，在急性损伤期间具有心脏保护作用。FTY 720长期使用是否具有心脏保护作用尚不清楚。在这里，我们报告了口服FTY 720对缺血/再灌注（I/R）损伤和SR-BI受体表达缺陷的HypoE小鼠（ApoeR 61 h/h/SRB 1-/-小鼠）的影响，这是一种饮食诱导的冠状动脉粥样硬化和心力衰竭模型。给C57 BL/6 J小鼠饮水中添加FTY 720（0.3mg/kg/d）。在离体心脏I/R损伤后，与对照组相比，这些小鼠显著改善了左心室（LV）发展压力并减小了梗死面积。随后，用口服FTY 720（0.05mg/kg/天）处理或不处理喂食高脂肪饮食（HFD）4周的ApoeR 61 h/h/SRB 1-/-小鼠。与对照组相比，这显著降低了死亡率（P<0.02），并导致更好的LV功能和更少的LV重塑，而没有降低高胆固醇血症和动脉粥样硬化。口服FTY 720减少血液淋巴细胞的数量，并增加循环、脾脏和淋巴结中CD 4 + Foxp 3 + T细胞（TcB）的百分比。FTY 720处理的小鼠在心脏中表现出增加的TGF-β和减少的IFN-γ表达。此外，CD 4表达增加，并且与参与天然Treg活性的分子如TGF-β和GITR密切相关。我们的数据表明，长期FTY 720治疗增强了心力衰竭小鼠的LV功能并延长了寿命。这些益处不是来自动脉粥样硬化保护，而是来自全身免疫抑制和心脏炎症的适度减少。
FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here we report the effects of oral FTY720 on ischemia/reperfusion (I/R) injury and in HypoE mice deficient in SR-BI receptor expression (ApoeR61h/h/SRB1–/– mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3mg/kg/day) to the drinking water of C57BL/6J mice. After ex vivo cardiac I/R injury these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61h/h/SRB1–/– mice fed a high fat diet (HFD) for 4 weeks were treated or not with oral FTY720 (0.05mg/kg/day). This sharply reduced mortality (P<0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ T cells (Tregs) in the circulation, spleen and lymph nodes. FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-β and GITR. Our data suggest that long-term FTY720-treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.