{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:29:38Z","timestamp":1776486578738,"version":"3.51.2"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:sec>\n            <jats:title>Objectives:<\/jats:title>\n            <jats:p>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\u2013dependent mechanisms of myocardial and vascular dysfunction in septic shock.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Design:<\/jats:title>\n            <jats:p>Prospective, randomized controlled experimental murine study and clinical cohort analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Setting:<\/jats:title>\n            <jats:p>University research laboratory and ICU at a tertiary-care center.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Patients:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Subjects:<\/jats:title>\n            <jats:p>C57Bl\/6J and genetic background\u2013matched microRNA-155 knockout mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Interventions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Measurements and Main Results:<\/jats:title>\n            <jats:p>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\u2013mediated inhibition of nitric oxide production and nitric oxide\u2013mediated 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our study demonstrates multiple new microRNA-155\u2013mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/ccm.0000000000003296","type":"journal-article","created":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T07:31:09Z","timestamp":1530689469000},"page":"e945-e954","source":"Crossref","is-referenced-by-count":27,"title":["MicroRNA-155 Amplifies Nitric Oxide\/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock"],"prefix":"10.1097","volume":"46","author":[{"given":"Francisco","family":"Vasques-N\u00f3voa","sequence":"first","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Internal Medicine, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."},{"name":"Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal."},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Instituto de Engenharia Biom\u00e9dica (INEB), University of Porto, Porto, Portugal."}]},{"given":"Tiago L.","family":"Laundos","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Instituto de Engenharia Biom\u00e9dica (INEB), University of Porto, Porto, Portugal."},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal."}]},{"given":"Rui J.","family":"Cerqueira","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Cardiothoracic Surgery, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."}]},{"given":"Catarina","family":"Quina-Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Cardiology, Hospital de Braga, Braga, Portugal."}]},{"given":"Ricardo","family":"Soares-dos-Reis","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Department of Biomedicine-Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal."}]},{"given":"Fabiana","family":"Baganha","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."}]},{"given":"Sara","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."}]},{"given":"Lu\u00eds","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."}]},{"given":"Francisco","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."}]},{"given":"Carlos","family":"Reguenga","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Department of Biomedicine-Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal."}]},{"given":"Wouter","family":"Verhesen","sequence":"additional","affiliation":[{"name":"Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands."}]},{"given":"F\u00e1tima","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Department of Pathology, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal."}]},{"given":"Jos\u00e9 Artur","family":"Paiva","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal."},{"name":"Department of Emergency and Intensive Care Medicine, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."}]},{"given":"Blanche","family":"Schroen","sequence":"additional","affiliation":[{"name":"Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands."}]},{"given":"Paulo","family":"Castro-Chaves","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Internal Medicine, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."},{"name":"Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal."}]},{"given":"Perp\u00e9tua","family":"Pinto-do-\u00d3","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Instituto de Engenharia Biom\u00e9dica (INEB), University of Porto, Porto, Portugal."},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal."}]},{"given":"Diana S.","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Instituto de Engenharia Biom\u00e9dica (INEB), University of Porto, Porto, Portugal."}]},{"given":"Stephane","family":"Heymans","sequence":"additional","affiliation":[{"name":"Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands."}]},{"given":"Adelino F.","family":"Leite-Moreira","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Cardiothoracic Surgery, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."}]},{"given":"Roberto","family":"Roncon-Albuquerque","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Emergency and Intensive Care Medicine, S\u00e3o Jo\u00e3o Hospital Center, Porto, Portugal."}]}],"member":"276","reference":[{"key":"R1-20230728","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"R2-20230728","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1097\/CCM.0b013e31827c09f8","article-title":"Benchmarking the incidence and mortality of severe sepsis in the United States.","volume":"41","author":"Gaieski","year":"2013","journal-title":"Crit Care 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