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

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Vasques Novoa, F (Author) FMUP; Laundos, TL (Author) Other; Cerqueira, RJ (Author) FMUP; Quina Rodrigues, C (Author) Other; Ricardo Soares dos Reis (Author) FMUP; Baganha, F (Author) Other; Ribeiro, S (Author) Other; Mendonça, Luís (Author) FMUP; Goncalves, F (Author) FMUP; reguenga, c (Author) FMUP; Verhesen, W (Author) Other; Carneiro F (Author) FMUP; Paiva, JA (Author) Other; Schroen, B (Author) Other; Castro-Chaves P (Author) FMUP; Perpetua Pinto do O (Author) ICBAS; Nascimento, DS (Author) ICBAS; Heymans, S (Author) Other; Leite-Moreira AF (Author) FMUP; Roncon-Albuquerque R Jr (Author) FMUP

Journal

Title: Critical Care Medicine

Vol. 46

Pages: E945-E954

ISSN: 0090-3493

Publisher: Wolters Kluwer Health

Indexing

ISI Web of Knowledge - 22 Citations

Scopus - 24 Citations

Other information

Authenticus ID: P-00P-GHY

DOI: 10.1097/ccm.0000000000003296

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10