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

Francisco Vasques-Novoa, Tiago L. Laundos, Rui J. Cerqueira, Catarina Quina-Rodrigues, Ricardo Soares-dos-Reis, Fabiana Baganha, Sara Ribeiro, Luis Mendonca, Francisco Goncalves, Carlos Reguenga, Wouter Verhesen, Fatima Carneiro, Jose Artur Paiva, Blanche Schroen, Paulo Castro-Chaves, Perpetua Pinto-do-O, Diana S. Nascimento, Stephane Heymans, Adelino F. Leite-Moreira, Roberto Roncon-Albuquerque*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

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.
Original languageEnglish
Pages (from-to)E945-E954
Number of pages10
JournalCritical Care Medicine
Volume46
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • angiotensin II
  • cardiomyopathy
  • endothelium
  • nitric oxide
  • septic shock
  • vasoplegia
  • SEVERE SEPSIS
  • DEPENDENT VASORELAXATION
  • MYOCARDIAL DYSFUNCTION
  • SYNTHASE
  • HEART
  • INJURY
  • MICE
  • THROMBOSPONDIN-1
  • PERMEABILITY
  • RESISTANCE

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