Luk Fu Sang, Kim Roy Y, Li Kang, Ching Daniel, Wong David K, Joshi Sunil K, Imhof Isabella, Honbo Norman, Hoover Holly, Zhu Bo-Qing, Lovett David H, Karliner Joel S, Raffai Robert L
Departments of *Surgery; and †Medicine, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA.
J Cardiovasc Pharmacol. 2016 Jan;67(1):47-56. doi: 10.1097/FJC.0000000000000312.
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.
METHODS/RESULTS: 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 6 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 postinfarction myocardial remodeling and chronic heart failure.
我们最近报道，在低表达清道夫受体BI（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）的低表达载脂蛋白E（Hypomorphic ApoE）小鼠中，使用FTY720进行免疫抑制可改善心脏功能并延长寿命。在本研究中，我们测试了FTY720对MI存活并随后发展为慢性心力衰竭的HypoE/SR-BI（–/–）小鼠心脏功能障碍的影响。
方法/结果：将HypoE/SR-BI（–/–）小鼠与Mx1-Cre转基因小鼠杂交，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MI。与我们之前的研究不同，通过诱导性Cre介导的HypoE等位基因基因修复以及将小鼠改为正常的普通饮食，高脂血症迅速得到逆转。在HFD期间存活的小鼠随后在饮用水中给予或不给予口服FTY720，并使用连续超声心动图监测左心室（LV）功能长达15周。在未治疗的小鼠中，LV性能逐渐恶化。尽管FTY720治疗最初并未阻止Cre介导的基因修复后6周小鼠心脏功能的下降，但到15周时，它几乎完全恢复了这些小鼠的正常LV功能。心力衰竭的逆转并非由于动脉粥样硬化减轻，因为两组小鼠的主动脉和冠状动脉粥样硬化负担实际上都增加到了相似的水平。相反，通过循环T和B淋巴细胞数量减少评估，FTY720导致全身免疫抑制。相比之下,FTY720并未增加在HFD喂养期间心脏中积累的T细胞或巨噬细胞的损失，但在血脂降低后不久确实增加了B细胞的损失。此外，FTY720有力地降低了心脏中基质金属蛋白酶-2的表达以及与先天免疫相关炎症相关的基因表达。
我们的数据表明，用FTY720进行免疫抑制可预防梗死后心肌重塑和慢性心力衰竭。
