title: Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure.
abstract: BACKGROUND
  Left ventricular dysfunction and heart failure are strongly associated in humans with increased circulating levels of proinflammatory cytokines, T cells, and soluble intercellular cell adhesion molecule 1 (ICAM1). In mice, infiltration of T cells into the left ventricle contributes to pathological cardiac remodeling, but the mechanisms regulating their recruitment to the heart are unclear. We hypothesized that ICAM1 regulates cardiac inflammation and pathological cardiac remodeling by mediating left ventricular T-cell recruitment and thus contributing to cardiac dysfunction and heart failure.
  
  
  RESULTS
  In a mouse model of pressure overload-induced heart failure, intramyocardial endothelial ICAM1 increased within 48 hours in response to thoracic aortic constriction and remained upregulated as heart failure progressed. ICAM1-deficient mice had decreased T-cell and proinflammatory monocyte infiltration in the left ventricle in response to thoracic aortic constriction, despite having numbers of circulating T cells and activated T cells in the heart-draining lymph nodes that were similar to those of wild-type mice. ICAM1-deficient mice did not develop cardiac fibrosis or systolic and diastolic dysfunction in response to thoracic aortic constriction. Exploration of the mechanisms regulating ICAM1 expression revealed that endothelial ICAM1 upregulation and T-cell infiltration were not mediated by endothelial mineralocorticoid receptor signaling, as demonstrated in thoracic aortic constriction studies in mice with endothelial mineralocorticoid receptor deficiency, but rather were induced by the cardiac cytokines interleukin 1β and 6.
  
  
  CONCLUSIONS
  ICAM1 regulates pathological cardiac remodeling by mediating proinflammatory leukocyte infiltration in the left ventricle and cardiac fibrosis and dysfunction and thus represents a novel target for treatment of heart failure.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Centro de Investigaciόn Biomédica, Universidad de Granada, Spain.
authors.forename: Ane M
authors.initials: AM
authors.lastname: Salvador
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
authors.forename: Tania
authors.initials: T
authors.lastname: Nevers
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Sackler School for Graduate studies, Tufts University School of Medicine, Boston, MA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velázquez
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
authors.forename: Mark
authors.initials: M
authors.lastname: Aronovitz
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Wang
authors.affiliation: Centro de Investigaciόn Biomédica, Universidad de Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Abadía Molina
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Sackler School for Graduate studies, Tufts University School of Medicine, Boston, MA.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Sackler School for Graduate studies, Tufts University School of Medicine, Boston, MA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Blanton
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Sackler School for Graduate studies, Tufts University School of Medicine, Boston, MA palcaide@tuftsmedicalcenter.org.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alcaide
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology* / Q000601:surgery; D062186:Arterial Pressure; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D003250:Constriction; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; C577686:interleukin-6, mouse; D018799:Intercellular Adhesion Molecule-1
keywords: adhesion molecules; heart failure; inflammation; remodeling