TY - JOUR
T1 - MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock
AU - Vasques-Novoa, Francisco
AU - Laundos, Tiago L.
AU - Cerqueira, Rui J.
AU - Quina-Rodrigues, Catarina
AU - Soares-dos-Reis, Ricardo
AU - Baganha, Fabiana
AU - Ribeiro, Sara
AU - Mendonca, Luis
AU - Goncalves, Francisco
AU - Reguenga, Carlos
AU - Verhesen, Wouter
AU - Carneiro, Fatima
AU - Paiva, Jose Artur
AU - Schroen, Blanche
AU - Castro-Chaves, Paulo
AU - Pinto-do-O, Perpetua
AU - Nascimento, Diana S.
AU - Heymans, Stephane
AU - Leite-Moreira, Adelino F.
AU - Roncon-Albuquerque, Roberto
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - angiotensin II
KW - cardiomyopathy
KW - endothelium
KW - nitric oxide
KW - septic shock
KW - vasoplegia
KW - SEVERE SEPSIS
KW - DEPENDENT VASORELAXATION
KW - MYOCARDIAL DYSFUNCTION
KW - SYNTHASE
KW - HEART
KW - INJURY
KW - MICE
KW - THROMBOSPONDIN-1
KW - PERMEABILITY
KW - RESISTANCE
U2 - 10.1097/CCM.0000000000003296
DO - 10.1097/CCM.0000000000003296
M3 - Article
C2 - 29979224
SN - 0090-3493
VL - 46
SP - E945-E954
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 9
ER -