Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion

Grégory Franck, Thomas Mawson, Grasiele Sausen, Manuel Salinas, Gustavo Santos Masson, Andrew Cole, Marina Beltrami-Moreira, Ioannis S Chatzizisis, Thibault Quillard, Yevgenia Tesmenitsky, Eugenia Shvartz, Galina K. Sukhova, Filip K. Swirski, Matthias Nahrendorf, Elena Aikawa, Kevin J. Croce, Peter Libby

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Rationale: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. Objective: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. Methods and Results: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). Conclusions: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

Original languageEnglish (US)
Pages (from-to)31-42
Number of pages12
JournalCirculation Research
Volume121
Issue number1
DOIs
StatePublished - Jun 23 2017

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Tunica Intima
Neutrophil Infiltration
Toll-Like Receptor 2
Neutrophils
Endothelial Cells
Thrombosis
Wounds and Injuries
Acute Coronary Syndrome
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Neutrophil Activation
Atherosclerotic Plaques
Hyaluronic Acid
Carotid Arteries
Ligation
Cell Death

Keywords

  • acute coronary syndromes
  • disturbed flow
  • endothelium
  • neutrophils
  • superficial erosion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice : Implications for Superficial Erosion. / Franck, Grégory; Mawson, Thomas; Sausen, Grasiele; Salinas, Manuel; Masson, Gustavo Santos; Cole, Andrew; Beltrami-Moreira, Marina; Chatzizisis, Ioannis S; Quillard, Thibault; Tesmenitsky, Yevgenia; Shvartz, Eugenia; Sukhova, Galina K.; Swirski, Filip K.; Nahrendorf, Matthias; Aikawa, Elena; Croce, Kevin J.; Libby, Peter.

In: Circulation Research, Vol. 121, No. 1, 23.06.2017, p. 31-42.

Research output: Contribution to journalArticle

Franck, G, Mawson, T, Sausen, G, Salinas, M, Masson, GS, Cole, A, Beltrami-Moreira, M, Chatzizisis, IS, Quillard, T, Tesmenitsky, Y, Shvartz, E, Sukhova, GK, Swirski, FK, Nahrendorf, M, Aikawa, E, Croce, KJ & Libby, P 2017, 'Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion', Circulation Research, vol. 121, no. 1, pp. 31-42. https://doi.org/10.1161/CIRCRESAHA.117.310694
Franck, Grégory ; Mawson, Thomas ; Sausen, Grasiele ; Salinas, Manuel ; Masson, Gustavo Santos ; Cole, Andrew ; Beltrami-Moreira, Marina ; Chatzizisis, Ioannis S ; Quillard, Thibault ; Tesmenitsky, Yevgenia ; Shvartz, Eugenia ; Sukhova, Galina K. ; Swirski, Filip K. ; Nahrendorf, Matthias ; Aikawa, Elena ; Croce, Kevin J. ; Libby, Peter. / Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice : Implications for Superficial Erosion. In: Circulation Research. 2017 ; Vol. 121, No. 1. pp. 31-42.
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N2 - Rationale: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. Objective: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. Methods and Results: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). Conclusions: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

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