Abstract
Cardiovascular diseases represent 1 of the main causes of death worldwide, and atherosclerosis
is 1 of the major contributors leading to ischemic heart disease. Macrophages actively
participate in all stages of atherosclerosis development, from plaque initiation to
the transition to vulnerable plaques. Macrophage apoptosis, in particular, has been
recognized as a critical step in the formation of the necrotic core, a key characteristic
of unstable lesions. In this review, we discuss the role of macrophage apoptosis and
clearance of apoptotic cells by efferocytosis in the development of atherosclerosis,
with particular emphasis on their contribution to the development of the necrotic
core and the clinical implications of this process for plaque stabilization. We consider
the molecular triggers of macrophage apoptosis during atherogenesis, the role of endoplasmic
reticulum (ER) stress, the roles of key cellular mediators of apoptosis and efferocytosis,
and mechanisms of defective efferocytosis in the progression of atherosclerotic plaques.
Finally, we discuss the important clinical implications of rapidly evolving macrophage
science, such as novel approaches to imaging vulnerable atherosclerotic plaques with
macrophage-sensitive positron emission tomography and magnetic resonance imaging,
the role of macrophages in mediating beneficial pleiotropic actions of lipid-lowering
therapies, and novel therapeutic modalities targeting ER stress, autophagy, and deficient
efferocytosis. Advances in understanding the critical role of macrophages in the progression
and destabilization of atherosclerosis have the potential to greatly improve the prevention
and management of atherosclerotic diseases over the next decade.
Résumé
Les maladies cardiovasculaires sont parmi les principales causes de décès à l’échelle
mondiale, tandis que l’athérosclérose constitue une des principales causes de cardiopathie
ischémique. Les macrophages participent activement à tous les stades de l’évolution
de l’athérosclérose, soit du processus de formation initiale de la plaque à la transition
vers la plaque athéromateuse instable. De façon plus précise, l’apoptose des macrophages
joue un rôle de premier plan dans la nécrose du centre de la plaque, une des principales
caractéristiques des lésions athéromateuses instables. Dans cet article, nous traitons
du rôle de l’apoptose des macrophages et de l’élimination des cellules apoptotiques
par efférocytose dans le processus athérosclérotique en insistant tout particulièrement
sur le rôle de ces mécanismes sur la nécrose du centre de la plaque athéromateuse
et l’instabilité de cette dernière. Nous discutons notamment des déclencheurs moléculaires
de l’apoptose des macrophages lors de l’athérogénèse, du rôle du stress du réticulum
endoplasmique (RE) et des médiateurs cellulaires clés de l’apoptose et de l’efférocytose,
ainsi que du mode d’évolution de la plaque athéromateuse en cas de diminution de l’efférocytose.
Enfin, nous abordons les importantes répercussions cliniques de l’évolution rapide
des connaissances sur les macrophages, notamment les nouvelles techniques d’imagerie
pour le dépistage des plaques athéromateuses instables à l’aide de la tomographie
par émission de positrons sensible aux macrophages et la résonnance magnétique, le
rôle des macrophages dans la médiation des effets pléiotropes bénéfiques des hypolipidémiants,
les nouveaux traitements ciblant le stress du RE, l’autophagie et la diminution de
l’efférocytose. L’amélioration de la compréhension du rôle essentiel joué par les
macrophages dans l’évolution et la déstabilisation de la plaque athéromateuse aura
vraisemblablement pour effet d’améliorer grandement les modalités de prévention et
de prise en charge de l’athérosclérose au cours de la prochaine décennie.
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Article info
Publication history
Published online: December 21, 2016
Accepted:
December 14,
2016
Received:
November 4,
2016
Footnotes
See page 309 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
