Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility
|Author||Bermúdez Pulgarín, Beatriz
|Department||Universidad de Sevilla. Departamento de Farmacología|
|Published in||Circulation, 132 (6), 490-501.|
Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact ...
Background Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. Methods and Results Hematopoietic Hck/Fgr–deficient, LDLr−/− chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as most prominent features. Despite a Ly6Chigh skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in-vitro and atherosclerotic plaques in–vivo, as assessed by intravital microscopy, flow cytometry and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence transmigrated dKO macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for dKO chimeras. Conclusions Hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase targeted intervention in plaque inflammation.
|Citation||Bermúdez Pulgarín, B., Medina, I., Cougoule, C., Drechsler, M. y Sluimer, J. (2015). Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility. Circulation, 132 (6), 490-501.|