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Canadian Journal of Cardiology

Macrophage Apoptosis and Necrotic Core Development in Atherosclerosis: A Rapidly Advancing Field with Clinical Relevance to Imaging and Therapy

  • Leticia Gonzalez
    Affiliations
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
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  • Bernardo Louis Trigatti
    Correspondence
    Corresponding author: Dr Bernardo Louis Trigatti, Department of Biochemistry and Biomedical Sciences, McMaster University, Thrombosis and Atherosclerosis Research Institute, Hamilton General Hospital Campus, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. Tel.: +1-905-521-2100 ×40744; fax: +1-905-522-9033.
    Affiliations
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author
Published:December 21, 2016DOI:https://doi.org/10.1016/j.cjca.2016.12.010

      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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