MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction During Acute Viral Myocarditis
MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction During Acute Viral Myocarditis
复制标题
DOI：
10.1161/circresaha.112.267443
复制
发表时间：
2012-08-03
影响因子：
20.1
通讯作者：
Heymans, Stephane
中科院分区：
文献类型：
--
作者：
Corsten, Maarten F.;Papageorgiou, Anna;Heymans, Stephane
理由：病毒性心肌炎是由对嗜心病毒的不良免疫反应引起的，在以前健康的人群中导致不可逆的心肌细胞破坏和心力衰竭。microrna在这一过程中的作用及其作为治疗靶点的作用尚不清楚。目的：鉴定参与病毒性心肌炎发病机制及易感性的microrna。方法与结果：对人心肌炎和柯萨奇病毒b3注射小鼠的心脏microrna进行了分析，并对心肌炎易感小鼠和不易感小鼠进行了纵向比较。病毒感染后小鼠对心肌炎的易感性不同，MicroRNA反应也不同。在人类和易感小鼠急性心肌炎期间，MicroRNA-155、-146b和-21持续且强烈上调。我们发现，在心肌炎期间，microRNA-155的表达主要局限于浸润性巨噬细胞和T淋巴细胞。在小鼠急性心肌炎期间，通过全身递送的LNA-anti-miR抑制microRNA-155可减轻单核巨噬细胞的心脏浸润，降低T淋巴细胞的活化，减轻心肌损伤。这些变化伴随着心脏炎症细胞中直接microRNA-155靶点PU.1的下调。在急性期之后的7周随访中，microRNA-155抑制降低了死亡率并改善了心功能。结论：我们的数据显示心脏microRNA失调是人和小鼠病毒性心肌炎的一个特征。炎症性microRNA-155在急性心肌炎期间上调，有助于心脏病毒感染的不良炎症反应，是病毒性心肌炎的潜在治疗靶点。（Circ Res. 2012; 111:415-425.）
Rationale: Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown.Objective: To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility.Methods and Results: Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up.Conclusions: Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis. (Circ Res. 2012; 111:415-425.)