Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.
Department of Internal Medicine, São João Hospital Center, Porto, Portugal.
Crit Care Med. 2018 Sep;46(9):e945-e954. doi: 10.1097/CCM.0000000000003296.
Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock.
Prospective, randomized controlled experimental murine study and clinical cohort analysis.
University research laboratory and ICU at a tertiary-care center.
Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting.
C57Bl/6J and genetic background-matched microRNA-155 knockout mice.
Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings.
We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings.
Our study demonstrates multiple new microRNA-155-mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.
感染性休克是一种危及生命的临床情况，与急性心肌和血管功能障碍有关，其病理生理学仍知之甚少。在此，我们研究了感染性休克中心肌和血管功能障碍的 microRNA-155 依赖性机制。
前瞻性、随机对照的实验性小鼠研究和临床队列分析。
大学研究实验室和三级保健中心的 ICU。
感染性休克患者、ICU 对照组和健康对照组。感染性和非感染性患者的死后心肌样本。接受冠状动脉旁路移植术患者的动脉环的离体评估。
C57Bl/6J 和遗传背景匹配的 microRNA-155 敲除小鼠。
使用两种感染性休克的小鼠模型。进行 microRNA-155 的基因缺失和药物抑制。使用小鼠和人动脉环进行离体肌电图研究。
我们确定 microRNA-155 是一种高度上调的多功能介质，可介导与败血症相关的心血管功能障碍。在人类中，血浆和心肌 microRNA-155 水平分别与败血症相关的死亡率和心脏损伤相关，而在小鼠模型中，microRNA-155 的缺失和药物抑制可减轻败血症相关的心血管功能障碍和死亡率。在感染性心肌中，microRNA-155 的上调主要由微血管内皮细胞支持。这促进了心肌微血管通透性和水肿、生物能恶化、收缩功能障碍、促炎和一氧化氮-cGMP-蛋白激酶 G 信号过度激活。在分离的心脏微血管内皮细胞中，microRNA-155 的上调显著促进 LPS 诱导的促炎细胞因子上调、白细胞黏附和一氧化氮过度产生。此外，我们发现 microRNA-155 通过直接靶向 CD47 作为败血症中心肌和血管收缩抑制的一种新机制，分别促进微血管内皮细胞和血管对血小板反应蛋白-1 介导的一氧化氮产生抑制和一氧化氮介导的血管舒张的敏感性降低。此外，microRNA-155 直接靶向血管紧张素 1 型受体，降低血管紧张素 II 反应性。microRNA-155 的缺失恢复了 LPS 暴露的动脉环中血管紧张素 II 和血小板反应蛋白-1 的血管反应性。
我们的研究表明，microRNA-155 介导的感染性休克相关心血管功能障碍的多种新机制，支持 microRNA-155 抑制在人类感染性休克中的转化潜力。
