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

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

来源：Critical Care Medicine, 2018, 46(9): E945-E954.

DOI：10.1097/CCM.0000000000003296

• angiotensin II
• cardiomyopathy
• endothelium
• nitric oxide
• septic shock
• vasoplegia

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.

• 出版日期2018-9