MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock

Objectives: 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. Design: Prospective, randomized controlled experimental murine study and clinical cohort analysis. Setting: University research laboratory and ICU at a tertiary-care center. Patients: 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. Subjects: C57Bl/6J and genetic background–matched microRNA-155 knockout mice. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/29S62lw). Supported, in part, with national funds by the Fundação para a Ciência e Tecnologia (FCT) (grants: PTDC/SAU-MET/116119/2009 and UID/IC/00051/2013); by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274) and individual fellowship (PD/BD/127997/2016) to Mr. Laundos; and Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000003 and NORTE-01-0145-FEDER-000012). Dr. Schroen’s institution received funding from the Netherlands Heart Foundation, Netherlands Organisation for Scientific Research, and she received support for article research from Netherlands Heart Foundation, Netherlands Organisation for Scientific Research. Dr. Roncon-Albuquerque’s institution received funding from European Society of Cardiology and Portuguese Society of Cardiology. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rra_jr@yahoo.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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