Martinet Wim, Coornaert Isabelle, Puylaert Pauline, De Meyer Guido R Y
Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
Front Pharmacol. 2019 Apr 4;10:306. doi: 10.3389/fphar.2019.00306. eCollection 2019.
Atherosclerosis is a chronic inflammatory disorder characterized by the gradual build-up of plaques within the vessel wall of middle-sized and large arteries. Over the past decades, treatment of atherosclerosis mainly focused on lowering lipid levels, which can be accomplished by the use of statins. However, some patients do not respond sufficiently to statin therapy and therefore still have a residual cardiovascular risk. This issue highlights the need for novel therapeutic strategies. As macrophages are implicated in all stages of atherosclerotic lesion development, they represent an important alternative drug target. A variety of anti-inflammatory strategies have recently emerged to treat or prevent atherosclerosis. Here, we review the canonical mechanisms of macrophage death and their impact on atherogenesis and plaque stability. Macrophage death is a prominent feature of advanced plaques and is a major contributor to necrotic core formation and plaque destabilization. Mechanisms of macrophage death in atherosclerosis include apoptosis, passive or accidental necrosis as well as secondary necrosis, a type of death that typically occurs when apoptotic cells are insufficiently cleared by neighboring cells via a phagocytic process termed efferocytosis. In addition, less-well characterized types of regulated necrosis in macrophages such as necroptosis, pyroptosis, ferroptosis, and parthanatos may occur in advanced plaques and are also discussed. Autophagy in plaque macrophages is an important survival pathway that protects against cell death, yet massive stimulation of autophagy promotes another type of death, usually referred to as autosis. Multiple lines of evidence indicate that a better insight into the different mechanisms of macrophage death, and how they mutually interact, will provide novel pharmacological strategies to resolve atherosclerosis and stabilize vulnerable, rupture-prone plaques.
动脉粥样硬化是一种慢性炎症性疾病，其特征是在中大型动脉的血管壁内逐渐形成斑块。在过去几十年中，动脉粥样硬化的治疗主要集中在降低血脂水平，这可以通过使用他汀类药物来实现。然而，一些患者对他汀类药物治疗反应不佳，因此仍然存在残余心血管风险。这个问题凸显了对新型治疗策略的需求。由于巨噬细胞参与动脉粥样硬化病变发展的各个阶段，它们是一个重要的替代性药物靶点。最近出现了多种抗炎策略来治疗或预防动脉粥样硬化。在这里，我们综述巨噬细胞死亡的经典机制及其对动脉粥样硬化发生和斑块稳定性的影响。巨噬细胞死亡是晚期斑块的一个突出特征，是坏死核心形成和斑块不稳定的主要促成因素。动脉粥样硬化中巨噬细胞死亡的机制包括凋亡、被动或意外坏死以及继发性坏死，继发性坏死是一种通常在凋亡细胞未被邻近细胞通过称为胞葬作用的吞噬过程充分清除时发生的死亡类型。此外，巨噬细胞中特征不太明确的调节性坏死类型，如坏死性凋亡、焦亡、铁死亡和PARP-1依赖性细胞坏死，可能发生在晚期斑块中，本文也将进行讨论。斑块巨噬细胞中的自噬是一种重要的存活途径，可防止细胞死亡，但自噬的大量刺激会促进另一种类型的死亡，通常称为自噬性细胞死亡。多条证据表明，更好地了解巨噬细胞死亡的不同机制及其相互作用方式，将为解决动脉粥样硬化和稳定易破裂的易损斑块提供新的药理学策略。
