MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock
Authors: Vasques-Nóvoa Francisco , Laundos Tiago L. , Cerqueira Rui J. , Quina-Rodrigues Catarina , Soares-dos-Reis Ricardo , Baganha Fabiana , Ribeiro Sara , Mendonça Luís , Gonçalves Francisco , Reguenga Carlos , Verhesen Wouter , Carneiro Fátima , Paiva José Artur , Schroen Blanche , Castro-Chaves Paulo , Pinto-do-Ó Perpétua , Nascimento Diana S. , Heymans Stephane , Leite-Moreira Adelino F. , Roncon-Albuquerque Roberto 
Published: July 2018

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.