Liver X receptor activation enhances CVB3 viral replication during myocarditis by stimulating lipogenesis
Liver X receptor activation enhances CVB3 viral replication during myocarditis by stimulating lipogenesis
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DOI：
10.1093/cvr/cvv157
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发表时间：
2015-07-01
影响因子：
10.8
通讯作者：
Heymans, Stephane
中科院分区：
文献类型：
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作者：
Papageorgiou, Anna-Pia;Heggermont, Ward;Heymans, Stephane
目的病毒性心肌炎（VM）是一种严重的心脏炎症，可导致猝死或充血性心力衰竭，在以前健康的成年人，没有有效的治疗。肝X受体（LXR）激动剂具有抗炎和降脂特性。本研究调查是否LXR激动剂T0901317可以调节病毒复制和心肌炎症在VM.Methods和结果（i）成年小鼠给予T0901317或车辆与炎症发作期间CVB 3病毒性心肌炎或（ii）治疗前2天CVB 3感染。与我们的预期相反，T0901317治疗没有改变CVB 3感染后的白细胞浸润;然而，与溶媒相比，T0901317预给药导致CVB 3感染后死亡率增加，心脏病毒存在增加，心肌细胞损伤增加。此外，我们发现脂肪酸合成酶（FAS）和固醇调节元件结合蛋白1c（SREBP-1c）与心脏中的CVB 3病毒载量相关，并且T0901317能够增强FAS和SREBP-1c的心脏表达。最后，我们表明，在体外，T0901317是能够夸大CVB 3介导的损伤Vero细胞，而FAS和SREBP-1C抑制剂减少病毒存在的CVB 3在新生儿cardiovascular cytos.Conclusion LXR激动不调节心脏炎症，但加剧病毒介导的心肌损伤VM通过刺激脂质生物合成和增强CVB 3复制。
Aims Viral myocarditis (VM) is severe cardiac inflammation that can result in sudden death or congestive heart failure in previously healthy adults, with no effective therapy. Liver X receptor (LXR) agonists have both anti-inflammatory and lipid-lowering properties. This study investigates whether LXR agonist T0901317 may modulate viral replication and cardiac inflammation during VM.Methods and results (i) Adult mice were administered T0901317 or vehicle with the onset of inflammation during CVB3 virus myocarditis or (ii) treated 2 days prior to CVB3 infection. Against what we expected, T0901317 treatment did not alter leucocyte infiltration after CVB3 infection; yet pre-administration with T0901317 resulted in increased mortality upon CVB3 infection, higher cardiac viral presence, and increased cardiomyocyte damage when compared with the vehicle. Furthermore, we show a correlation of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) with CVB3 viral load in the heart and that T0901317 is able to enhance the cardiac expression of FAS and SREBP-1c. Finally, we show in vitro that T0901317 is able to exaggerate CVB3-mediated damage of Vero cells, whereas inhibitors of FAS and the SREBP-1c reduce the viral presence of CVB3 in neonatal cardiomyocytes.Conclusion LXR agonism does not modulate cardiac inflammation, but exacerbates virus-mediated myocardial damage during VM by stimulating lipid biosynthesis and enhancing CVB3 replication.