title: TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion.
abstract: OBJECTIVE
  Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion.
  
  
  RESULTS
  Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques. In vitro, TLR2 ligands (including hyaluronan, a matrix macromolecule abundant in eroded lesions) induced endothelial stress, characterized by reactive oxygen species production, endoplasmic reticulum (ER) stress, and apoptosis. Co-incubation of neutrophils with endothelial cells (ECs) potentiated these effects and induced EC apoptosis and detachment. We then categorized human atherosclerotic plaques (n = 56) based on morphologic features associated with superficial erosion, 'stable' fibrotic, or 'vulnerable' lesions. Morphometric analyses of the human atheromata localized neutrophils and neutrophil extracellular traps (NETs) near clusters of apoptotic ECs in smooth muscle cell (SMC)-rich plaques. The number of luminal apoptotic ECs correlated with neutrophil accumulation, amount of NETs, and TLR2 staining in SMC-rich plaques, but not in 'vulnerable' atheromata.
  
  
  CONCLUSIONS
  These in vitro observations and analyses of human plaques indicate that TLR2 stimulation followed by neutrophil participation may render smooth muscle cell-rich plaques susceptible to superficial erosion and thrombotic complications by inducing ER stress, apoptosis, and favouring detachment of EC.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA INSERM, UMR957, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Haniel Alves
authors.initials: HA
authors.lastname: Araújo
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Franck
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Shvartz
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Sukhova
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA plibby@partners.org.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D054058:Acute Coronary Syndrome / Q000209:etiology / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005452:Fluoresceins / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000503:physiopathology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012422:Rupture, Spontaneous / Q000503:physiopathology; D013312:Stress, Physiological / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C110400:2',7'-dichlorodihydrofluorescein diacetate; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016207:Cytokines; D005452:Fluoresceins; D005456:Fluorescent Dyes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051195:Toll-Like Receptor 2; D051742:Transcription Factor CHOP; D006820:Hyaluronic Acid; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D019272:Leukocyte Elastase; D020169:Caspases
keywords: Endothelial cells; Hyaluronan; NET; Neutrophil; Superficial erosion; TLR2