Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis.
Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis.
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DOI：
10.1097/fjc.0000000000000312
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发表时间：
2016-01
影响因子：
3
通讯作者：
Raffai RL
中科院分区：
文献类型：
--
作者：
Luk FS;Kim RY;Li K;Ching D;Wong DK;Joshi SK;Imhof I;Honbo N;Hoover H;Zhu BQ;Lovett DH;Karliner JS;Raffai RL
我们最近报道，FTY720 的免疫抑制可改善缺乏清道夫受体 BI 型表达的亚形 ApoE 小鼠（也称为饮食诱导的冠状动脉粥样硬化和心肌梗死 (MI) 的 HypoE/SR-BI−/− 小鼠模型）的心脏功能并延长寿命。在这项研究中，我们测试了 FTY720 对 HypoE/SR-BI−/− 小鼠心脏功能障碍的影响，这些小鼠在 MI 中存活并随后发展为慢性心力衰竭。 HypoE/SR-BI−/− 小鼠与 Mx1-Cre 转基因小鼠交配，并给后代喂食高脂饮食 (HFD) 3.5 周，以引发高脂血症、冠状动脉粥样硬化和复发性心肌梗死。与我们之前的研究相反，通过诱导性 Cre 介导的 HypoE 等位基因基因修复并将小鼠改为正常饮食，高脂血症迅速逆转。在 HFD 期间幸存的小鼠随后被口服 FTY720 和饮用水（或不加水），并使用连续超声心动图监测左心室 (LV) 功能长达 15 周。在未经治疗的小鼠中，左心室性能逐渐恶化。虽然 FTY720 治疗最初并没有阻止 Cre 介导的基因修复后 6 周的小鼠心脏功能下降，但到 15 周时，它几乎完全恢复了这些小鼠的正常左心室功能。心力衰竭的逆转并不是动脉粥样硬化减少的结果，因为两组小鼠的主动脉和冠状动脉粥样硬化的负担实际上增加到相似的水平。相反，通过循环 T 和 B 淋巴细胞数量的减少来评估，FTY720 引起了全身免疫抑制。相比之下，FTY720并没有增加HFD喂养期间心脏中积累的T细胞或巨噬细胞的损失，但它确实增加了血浆脂质降低后不久的B细胞的损失。此外，FTY720 还可有效降低基质金属蛋白酶-2 和心脏先天免疫相关炎症相关基因的表达。我们的数据表明，FTY720 的免疫抑制可预防梗死后心肌重塑和慢性心力衰竭。
We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI−/− mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI−/− mice that survive MI and subsequently develop chronic heart failure. HypoE/SR-BI−/− mice were bred to Mx1-Cre transgenic mice and offspring were fed a high fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice six weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart. Our data demonstrate that immunosuppression with FTY720 prevents post-infarction myocardial remodeling and chronic heart failure.