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沙库巴曲/缬沙坦通过PI3K/AKT通路抑制CVB3诱导的病毒性心肌炎小鼠中病毒复制及心肌细胞凋亡
刘文芹
许竞
刘维克
陈奕琏
邱依旋
林元楠
李岳春
作者及单位信息
·
DOI： 10.3760/cma.j.cn112309-20230211-00027
Sacubitril/valsartan inhibit viral replication and cardiomyocyte apoptosis in mice with CVB3-induced viral myocarditis via PI3K/AKT pathway
Liu Wenqin
Xu Jing
Liu Weike
Chen Yilian
Qiu Yixuan
Lin Yuannan
Li Yuechun
Authors Info & Affiliations
Liu Wenqin
Digital Subtraction Angiography Center, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
Xu Jing
Cardiovascular Medicine Ward 2, Jinhua Municipal Central Hospital, Jinhua 321000, China
Liu Weike
Department of Cardiology, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
Chen Yilian
Department of Cardiology, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
Qiu Yixuan
Department of Cardiology, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
Lin Yuannan
Department of Cardiology, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
Li Yuechun
Department of Cardiology, the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou 325000, China
·
DOI： 10.3760/cma.j.cn112309-20230211-00027
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摘要

目的观察沙库巴曲/缬沙坦(LCZ696)对柯萨奇病毒B3(CVB3)诱导的病毒性心肌炎(VMC)小鼠中病毒复制及心肌细胞凋亡的作用，并探究其具体机制。

方法40只BALB/c小鼠随机分成4组( n＝10)：Sham组、Sham+LCZ696组、VMC组和VMC+LCZ696组。向BALB/c小鼠腹腔注射10 6 TCID 50/ml浓度CVB3 0.1 ml建立VMC模型，Sham组注射等量生理盐水，病毒注射当天被定义为第0天。每天60 mg/kg沙库巴曲/缬沙坦进行灌胃治疗，连续7 d。统计小鼠生存率；小动物超声检测小鼠心功能；ELISA法检测肌酸激酶MB同工酶(CK-MB)水平；Western blot检测小鼠心脏促炎因子(IL-6、TNF-α)，凋亡相关蛋白(caspase-3、cleaved-caspase-3、Bax、Bcl-2)，CVB3病毒表面蛋白(VP-1)及相关通路蛋白(p-PI3K/PI3K、p-AKT/AKT)水平；PCR检测小鼠心脏中CVB3 mRNA水平；HE染色检测小鼠心脏炎性细胞浸润水平；TUNEL检测小鼠心脏组织中细胞凋亡水平。

结果与Sham组相比，VMC组生存率下降，心功能指标(LVEDd、LVEDs、LVEF)减退( P<0.05)。VMC组小鼠血清CK-MB及心脏中IL-6、TNF-α、cleaved-caspase-3/caspase-3、Bax/Bcl-2、VP-1、CVB3 mRNA显著上升( P<0.05)，同时AKT表达增多，而其磷酸化水平下降( P<0.05)，细胞凋亡增多。LCZ696逆转了以上变化，表现为生存率上升，心功能改善( P<0.05)，心脏炎症、凋亡与复制水平下调( P<0.05)，p-AKT的水平上升( P<0.05)。沙库巴曲/缬沙坦对正常小鼠生存率、心功能、心肌损伤、心脏炎症、凋亡、病毒复制水平以及PI3K/AKT通路相关蛋白均无明显影响。

结论沙库巴曲/缬沙坦可通过调控PI3K/AKT通路，显著抑制VMC小鼠的心肌细胞凋亡水平，并降低CVB3在小鼠心脏中的病毒复制水平，抑制心肌炎症，从而改善小鼠心功能及生存率。

沙库巴曲/缬沙坦;病毒性心肌炎;PI3K/AKT通路;病毒复制;凋亡
ABSTRACT

ObjectiveTo observe the effects of sacubitril/valsartan (LCZ696) on viral replication and cardiomyocyte apoptosis in mice with coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) and to analyze the underlying mechanisms.

MethodsForty BALB/c mice were randomly divided into four groups with 10 in each group: Sham, Sham+ LCZ696, VMC, and VMC+ LCZ696 groups. VMC model was established by intraperitoneal injection of 0.1 ml of CVB3 with a concentration of 10 6 TCID 50/ml into BALB/c mice, while the sham intervention was an equal volume of saline. The day of virus injection was defined as day 0. LCZ696 was administered by gavage at a dose of 60 mg/kg every day for seven consecutive days starting from day 1. Mouse survival rates were calculated. Echocardiography was used to evaluate the cardiac function of mice. The level of creatine kinase-MB (CK-MB) was detected by ELISA. Western blot was used to detect the levels of inflammatory cytokines (IL-6, TNF-α), apoptosis-related proteins (caspase-3, cleaved-caspase-3, Bax, Bcl-2), CVB3 surface protein (VP-1) and p-AKT/AKT in the hearts of mice. CVB3 mRNA in mouse hearts was measured by PCR. Inflammatory cell infiltration and cell apoptosis in mouse hearts were observed by HE staining and TUNEL staining, respectively.

ResultsCompared with the Sham group, the mice in the VMC group had a decreased survival rate and impaired cardiac function ( P<0.05). The levels of CK-MB, IL-6, TNF-α, cleaved-caspase-3/caspase-3, Bax/Bcl-2, VP-1, and CVB3 mRNA in the hearts of VMC mice increased significantly ( P<0.05), accompanied by increased expression of AKT, decreased phosphorylation of AKT ( P<0.05) and increased cell apoptosis. LCZ696 reversed the above changes. It could increase the survival rate, improve the cardiac function ( P<0.05), decrease cardiac inflammation, cell apoptosis and viral replication ( P<0.05), and increase the phosphorylation of AKT ( P<0.05). LCZ696 had no significant effects on the survival rate, cardiac function, myocardial injury, cardiac inflammation, cell apoptosis, viral replication or the expression of PI3K/AKT signaling pathway-related proteins in normal mice.

ConclusionsLCZ696 could significantly inhibit cardiomyocyte apoptosis and reduce CVB3 replication in the hearts of VMC mice by regulating the PI3K/AKT pathway, thereby improving mouse cardiac function and survival rate.

Sacubitril/valsartan (LCZ696);Viral myocarditis;PI3K/AKT pathway;Viral replication;Apoptosis
Li Yuechun, Email: mocdef.aabnis0891nuhceuyil, Tel: 0086-577-88832693

Liu Wenqin and Xu Jing are contributed equally to the article

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引用本文

刘文芹,许竞,刘维克,等. 沙库巴曲/缬沙坦通过PI3K/AKT通路抑制CVB3诱导的病毒性心肌炎小鼠中病毒复制及心肌细胞凋亡[J]. 中华微生物学和免疫学杂志,2023,43(07)：547-554.

DOI:10.3760/cma.j.cn112309-20230211-00027

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病毒性心肌炎(viral myocarditis, VMC)是由柯萨奇病毒B3(coxsackievirus B3, CVB3)、新型冠状病毒、细小病毒B19等感染所致的心肌组织炎性病变 [ 1 , 2 ]，是导致年轻患者心衰最主要的原因之一 [ 2 , 3 ]。目前VMC的治疗尚无特效药物，其主要原因为VMC具体发病机制并不完全清楚。
细胞凋亡与病毒复制是VMC中的重要病理过程，且两者之间关系紧密 [ 4 ]。Ventéo等 [ 5 ]研究证实，CVB3等肠道病毒较其他类型病毒与VMC中心肌细胞的凋亡水平联系更为密切。在VMC发生发展早期，病毒的直接攻击是造成心肌损伤的主要原因 [ 6 ]。CVB3感染心肌细胞后在细胞内增殖并通过半胱氨酸天冬氨酸蛋白酶(caspase)、线粒体介导的凋亡等多种途径导致心肌细胞死亡 [ 7 , 8 , 9 ]。在重症VMC中心肌细胞凋亡率增高不仅与致命性心力衰竭的发生密切相关，而且与VMC向慢性扩张型心肌病的转变密切相关 [ 10 ]。使用TGF-β可在早期抑制CVB3的复制并减轻其介导的自身免疫应答 [ 11 ] 。因此，如何在疾病的早期抑制病毒复制与细胞凋亡，提高心肌细胞存活率，阻止疾病进一步发生发展，在VMC的治疗中显得尤其重要。
沙库巴曲/缬沙坦(LCZ696)是血管紧张素受体缬沙坦与肾上腺素酶抑制剂沙库巴曲组成的药物，可显著提高射血分数降低型心衰(HFrEF)患者左心室射血分数(LVEF)，降低心衰持续时间，改善心室重塑 [ 2 , 12 , 13 , 14 ] 。沙库巴曲/缬沙坦还被证实具有抗心肌细胞凋亡的能力。Ge等 [ 15 ]及Belali等 [ 16 ]的研究表明沙库巴曲/缬沙坦可抑制糖尿病心肌病小鼠心脏中炎症、氧化应激及细胞凋亡水平。Liang等 [ 17 ]发现其具有减弱阿霉素诱导的心肌细胞凋亡作用。还有研究发现沙库巴曲/缬沙坦保护VMC小鼠心功能可能与Drp1介导的线粒体功能相关 [ 18 ] 。然而，目前沙库巴曲/缬沙坦与CVB3复制的研究鲜见报道，结合病毒与细胞凋亡的关联，我们认为沙库巴曲/缬沙坦可能与CVB3的复制有关。
PI3K/AKT通路在VMC的细胞凋亡与病毒复制中发挥关键作用。Li等 [ 19 ]研究发现CVB3诱导的心肌炎中，PI3K/AKT通路与尼古丁介导的抗心肌细胞凋亡作用相关，在VMC动物及细胞模型中尼古丁通过上调AKT的磷酸化而抑制细胞的凋亡。Chang等 [ 20 ]用ZSTK474抑制PI3K后可减轻CVB3刺激的HeLa细胞中自噬水平，并抑制病毒的复制。使用MK2206抑制p-AKT水平则加重了病毒感染诱导的自噬水平。在CVB3感染的H9C2细胞模型中，心脏祖细胞来源的外泌体可通过升高AKT1的磷酸化水平而抑制VP-1表达，抑制细胞的凋亡 [ 21 ]。但沙库巴曲/缬沙坦是否可通过调控PI3K/AKT通路影响VMC中病毒复制及心肌细胞凋亡尚不确定。本研究使用沙库巴曲/缬沙坦治疗早期VMC小鼠，旨在明确其对CVB3诱导的VMC心肌细胞凋亡和病毒复制水平的作用，探讨该作用是否通过PI3K/AKT通路实现，以期为VMC的临床治疗提供新的研究方向。
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备注信息
A
李岳春，Email： mocdef.aabnis0891nuhceuyil，电话：0577-88832693
B

刘文芹和许竞对本文有同等贡献

C

刘文芹、许竞：实验操作、数据整理、论文撰写；刘维克、陈奕琏、邱依旋、林元楠：数据采集、统计分析、技术支持；李岳春：实验设计、研究指导、经费支持

D
所有作者声明无利益冲突
E
浙江省基础公益研究计划项目 (LY22H020009)
国家自然科学基金 (81870281)
温州市科技计划项目 (Y20210137)
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