MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock
| Autor: | Catarina Quina-Rodrigues, Blanche Schroen, Diana S. Nascimento, Fabiana Baganha, Tiago L. Laundos, Adelino F. Leite-Moreira, F. J. T. Goncalves, Sara Ribeiro, Francisco Vasques-Nóvoa, Rui J Cerqueira, Wouter Verhesen, Fátima Carneiro, Ricardo Soares-dos-Reis, Stephane Heymans, Roberto Roncon-Albuquerque, José Artur Paiva, Carlos Reguenga, Luís Mendonça, Paulo Castro-Chaves, Perpétua Pinto-do-Ó |
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| Přispěvatelé: | Cardiologie, RS: CARIM - R2.02 - Cardiomyopathy, MUMC+: MA Med Staf Spec Cardiologie (9) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine 030204 cardiovascular system & hematology Pharmacology angiotensin II Critical Care and Intensive Care Medicine Random Allocation chemistry.chemical_compound 0302 clinical medicine Vasoplegia Medicine SYNTHASE Prospective Studies Cyclic GMP Cells Cultured MYOCARDIAL DYSFUNCTION Shock Septic Pathophysiology medicine.anatomical_structure Shock (circulatory) THROMBOSPONDIN-1 HEART medicine.symptom Signal Transduction Endothelium endothelium DEPENDENT VASORELAXATION Nitric oxide 03 medical and health sciences nitric oxide Thrombospondin 1 INJURY Animals Humans PERMEABILITY business.industry Septic shock Myocardium Endothelial Cells medicine.disease Angiotensin II Mice Inbred C57BL SEVERE SEPSIS MicroRNAs MICE 030104 developmental biology chemistry Blood Vessels septic shock vasoplegia business cardiomyopathy RESISTANCE |
| Zdroj: | Critical Care Medicine, 46(9), E945-E954. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 1530-0293 0090-3493 |
| DOI: | 10.1097/CCM.0000000000003296 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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