Francisco Vasques-Nóvoa1,2,3,4,5, Tiago L Laundos4,5,6, Rui J Cerqueira1,7, Catarina Quina-Rodrigues1,8, Ricardo Soares-Dos-Reis4,9,10, Fabiana Baganha1, Sara Ribeiro1, Luís Mendonça1, Francisco Gonçalves1, Carlos Reguenga4,9,10, Wouter Verhesen11, Fátima Carneiro4,12,13, José Artur Paiva3,14, Blanche Schroen11, Paulo Castro-Chaves1,2,3, Perpétua Pinto-do-Ó4,5,6, Diana S Nascimento4,5, Stephane Heymans11, Adelino F Leite-Moreira1,7, Roberto Roncon-Albuquerque1,14. 1. Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal. 2. Department of Internal Medicine, São João Hospital Center, Porto, Portugal. 3. Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal. 4. Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. 5. Instituto de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal. 6. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal. 7. Department of Cardiothoracic Surgery, São João Hospital Center, Porto, Portugal. 8. Department of Cardiology, Hospital de Braga, Braga, Portugal. 9. Department of Biomedicine-Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal. 10. Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal. 11. Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands. 12. Department of Pathology, São João Hospital Center, Porto, Portugal. 13. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal. 14. Department of Emergency and Intensive Care Medicine, São João Hospital Center, Porto, Portugal.
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.
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 humanseptic shock.
Authors: Mahmoud Abdellatif; Viktoria Trummer-Herbst; Franziska Koser; Sylvère Durand; Rui Adão; Francisco Vasques-Nóvoa; Johanna K Freundt; Julia Voglhuber; Maria-Rosaria Pricolo; Michael Kasa; Clara Türk; Fanny Aprahamian; Elías Herrero-Galán; Sebastian J Hofer; Tobias Pendl; Lavinia Rech; Julia Kargl; Nathaly Anto-Michel; Senka Ljubojevic-Holzer; Julia Schipke; Christina Brandenberger; Martina Auer; Renate Schreiber; Chintan N Koyani; Akos Heinemann; Andreas Zirlik; Albrecht Schmidt; Dirk von Lewinski; Daniel Scherr; Peter P Rainer; Julia von Maltzahn; Christian Mühlfeld; Marcus Krüger; Saša Frank; Frank Madeo; Tobias Eisenberg; Andreas Prokesch; Adelino F Leite-Moreira; André P Lourenço; Jorge Alegre-Cebollada; Stefan Kiechl; Wolfgang A Linke; Guido Kroemer; Simon Sedej Journal: Sci Transl Med Date: 2021-02-10 Impact factor: 19.319
Authors: Francisco Vasques-Nóvoa; António Angélico-Gonçalves; José M G Alvarenga; João Nobrega; Rui J Cerqueira; Jennifer Mancio; Adelino F Leite-Moreira; Roberto Roncon-Albuquerque Journal: ESC Heart Fail Date: 2022-02-11