Grégory Franck1, Thomas Mawson1, Grasiele Sausen1, Manuel Salinas1, Gustavo Santos Masson1, Andrew Cole1, Marina Beltrami-Moreira1, Yiannis Chatzizisis1, Thibault Quillard1, Yevgenia Tesmenitsky1, Eugenia Shvartz1, Galina K Sukhova1, Filip K Swirski1, Matthias Nahrendorf1, Elena Aikawa1, Kevin J Croce1, Peter Libby2. 1. From the Department of Cardiovascular Medicine (G.F., T.M., G.S., M.S., A.C., M.B.-M., Y.C., T.Q., Y.T., E.S., G.K.S., E.A., K.J.C., P.L.), and Center for Interdisciplinary Cardiovascular Sciences (E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston (G.S.M., F.K.S., M.N.); and Department of Engineering and Technology, College of Engineering and Computing, Nova Southeastern University, Fort Lauderdale, FL (M.S.). 2. From the Department of Cardiovascular Medicine (G.F., T.M., G.S., M.S., A.C., M.B.-M., Y.C., T.Q., Y.T., E.S., G.K.S., E.A., K.J.C., P.L.), and Center for Interdisciplinary Cardiovascular Sciences (E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston (G.S.M., F.K.S., M.N.); and Department of Engineering and Technology, College of Engineering and Computing, Nova Southeastern University, Fort Lauderdale, FL (M.S.). plibby@bwh.harvard.edu.
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.
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.
Authors: Kara A Scheibner; Michael A Lutz; Sada Boodoo; Matthew J Fenton; Jonathan D Powell; Maureen R Horton Journal: J Immunol Date: 2006-07-15 Impact factor: 5.422
Authors: Eneida Villanueva; Srilakshmi Yalavarthi; Celine C Berthier; Jeffrey B Hodgin; Ritika Khandpur; Andrew M Lin; Cory J Rubin; Wenpu Zhao; Stephen H Olsen; Matthew Klinker; David Shealy; Michael F Denny; Joel Plumas; Laurence Chaperot; Matthias Kretzler; Allen T Bruce; Mariana J Kaplan Journal: J Immunol Date: 2011-05-25 Impact factor: 5.422
Authors: T Sumi; A Yamashita; S Matsuda; S Goto; K Nishihira; E Furukoji; H Sugimura; H Kawahara; T Imamura; K Kitamura; S Tamura; Y Asada Journal: J Thromb Haemost Date: 2010-03-04 Impact factor: 5.824
Authors: Mete Civelek; Elisabetta Manduchi; Rebecca J Riley; Christian J Stoeckert; Peter F Davies Journal: Circ Res Date: 2009-08-06 Impact factor: 17.367
Authors: Andreas Mangold; Sherin Alias; Thomas Scherz; Thomas Hofbauer; Johannes Jakowitsch; Adelheid Panzenböck; Daniel Simon; Daniela Laimer; Christine Bangert; Andreas Kammerlander; Julia Mascherbauer; Max-Paul Winter; Klaus Distelmaier; Christopher Adlbrecht; Klaus T Preissner; Irene M Lang Journal: Circ Res Date: 2014-12-29 Impact factor: 17.367
Authors: E Durand; A Scoazec; A Lafont; J Boddaert; A Al Hajzen; F Addad; M Mirshahi; M Desnos; A Tedgui; Z Mallat Journal: Circulation Date: 2004-05-17 Impact factor: 29.690
Authors: Kemal M Akat; Youngmin A Lee; Arlene Hurley; Pavel Morozov; Klaas Ea Max; Miguel Brown; Kimberly Bogardus; Anuoluwapo Sopeyin; Kai Hildner; Thomas G Diacovo; Markus F Neurath; Martin Borggrefe; Thomas Tuschl Journal: JCI Insight Date: 2019-04-11
Authors: Grégory Franck; Thomas L Mawson; Eduardo J Folco; Roberto Molinaro; Victoria Ruvkun; Daniel Engelbertsen; Xin Liu; Yevgenia Tesmenitsky; Eugenia Shvartz; Galina K Sukhova; Jean-Baptiste Michel; Antonino Nicoletti; Andrew Lichtman; Denisa Wagner; Kevin J Croce; Peter Libby Journal: Circ Res Date: 2018-03-23 Impact factor: 17.367