• Francisco Vasques-Nóvoa, Tiago L Laundos, Rui J Cerqueira, Catarina Quina-Rodrigues, Ricardo Soares-Dos-Reis, Fabiana Baganha, Sara Ribeiro, Luís Mendonça, Francisco Gonçalves, Carlos Reguenga, Wouter Verhesen, Fátima Carneiro, José Artur Paiva, Blanche Schroen, Paulo Castro-Chaves, Perpétua Pinto-do-Ó, Diana S Nascimento, Stephane Heymans, Adelino F Leite-Moreira, and Roberto Roncon-Albuquerque.
• Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.
• Crit. Care Med. 2018 Sep 1; 46 (9): e945-e954.

ObjectivesSeptic 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.DesignProspective, randomized controlled experimental murine study and clinical cohort analysis.SettingUniversity research laboratory and ICU at a tertiary-care center.PatientsSeptic 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.SubjectsC57Bl/6J and genetic background-matched microRNA-155 knockout mice.InterventionsTwo 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.Measurements And Main ResultsWe 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.ConclusionsOur 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.

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