miRNA-185/SCD1通过调节心肌细胞内脂肪酸代谢在病毒性心肌炎病毒复制中的作用和机制研究

Viral replication is the key factor in the development of viral myocarditis (VMC). Coxsackievirus B3 (CVB3) is the common pathogen. However, the mechanism of viral replication in myocardial cells remains unclear. The recent researches revealed that myocardial fatty acid metabolism was associated with viral replication. We newly found that Stearoyl-CoA desaturase-1 (SCD1) was increased on myocardial cells under CVB3 infection, and the expression of SCD1 was regulated by miRNA-185. Down-regulating SCD1 expression resulted in the reduced CVB3 replications in myocardial cells. Thus, we speculated that SCD1 regulated by miRNA-185 was involved in the CVB3 replications in VMC. In the present study, after establishing VMC mouse model by CVB3, we transfect the miRNA-185 oligonucleotides or siRNA into VMC mice respectively, and measure the disease severity，the SCD1 expression, fatty acid metabolism, viral replication, the formation of lipid raft / lipid droplets, and the alteration of signal pathway in myocardial cell. The data would reveal the new pathogenesis of VMC and provide a new target for VMC treatment.

病毒复制是介导病毒性心肌炎（VMC）疾病进展的重要因素。柯萨奇病毒B3（CVB3）是导致VMC最常见的病毒。然而，CVB3在心肌细胞中复制的机制至今尚未完全阐明。近来研究认为心肌细胞内脂肪酸代谢与病毒复制相关。本课题组最近发现参与脂肪酸代谢的主要分子硬脂酰辅酶A脱氢酶1（SCD1）的表达在心肌感染CVB3后明显升高，其表达受miRNA-185调控，而下调SCD1表达可以明显抑制CVB3复制。因此，我们推测miRNA-185靶向调节心肌细胞SCD1表达，可以特异性调控心肌细胞中病毒复制。本研究拟采用CVB3建立VMC小鼠模型，在体内外利用转染技术导入miRNA-185模拟物/抑制剂，检测其疾病进展、心肌细胞SCD1表达、脂肪酸代谢、病毒复制、脂阀/脂肪小体形成和相关信号分子表达，探讨miRNA-185/SCD1在VMC病毒复制中的作用和机制，揭示VMC新的发病机制，为VMC提供新的治疗靶点。

病毒复制是介导病毒性心肌炎（VMC）疾病进展的重要因素。柯萨奇病毒B3（CVB3）是导致VMC最常见的病毒。然而，CVB3在心肌细胞中复制的机制至今尚未完全阐明。心肌细胞内脂肪酸代谢与病毒复制的直接调控密切相关。本研究通过筛选VMC小鼠心肌细胞中参与脂肪酸代谢相关蛋白（SREBP2、SRBⅠ、SRBⅡ和SCD1），发现仅SCD1的表达在心肌细胞感染CVB3后明显升高，并且SCD1的表达水平与VMC小鼠心肌病理损伤密切相关。miRNA-185通过调节心肌细胞SCD1表达进而抑制CVB3病毒在心肌细胞内的复制。miRNA-185和SCD1可能为VMC早期治疗的新靶点。此外，本研究表明血管紧张素受体脑啡肽酶抑制剂（Sac/Val）可以降低EAM心脏Th17细胞分化，同时通过sGC/NF-κB通路改善心肌炎的疾病严重程度。血管紧张素受体脑啡肽酶抑制剂（Sac/Val）可能为心肌炎的潜在治疗药物。前蛋白转化酶枯草杆菌蛋白酶/kexin9型（PCSK9）通过调节Th17和Treg细胞分化参与实验性自身免疫性心肌炎疾病进展，有望为心肌炎提供新的治疗策略。