期刊
EUROPEAN HEART JOURNAL
卷 36, 期 22, 页码 1394-+出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehv044
关键词
Superficial erosion; Endothelial cells; TLR2; Neutrophil; Hyaluronan; NET
资金
- National Heart, Lung, and Blood Institute [R01 HL080472]
- Donald W. Reynolds Foundation
- Fundacao-opara o Amparo de Pesquisas do Estado de Sao Paulo, Brazil
- FundacaoLemann, Sao Paulo, Brazil
- Harold M. English Fellowship Fund from the Harvard Medical School
- Fondation Bettencourt Schueller
- Fondation pour la Recherche Medicale, Paris, France
Aims 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. Methods and results Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques. In vitro, TLR2 ligands (including hyaluronan, a matrixmacromolecule 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. Conclusion 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.
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