Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets.

Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis - the efficient clearance of dead cells by macrophages - is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies.

Regulated Necrosis in Atherosclerosis.

During atherosclerosis, lipid-rich plaques are formed in large- and medium-sized arteries, which can reduce blood flow to tissues. This situation becomes particularly precarious when a plaque develops an unstable phenotype and becomes prone to rupture. Despite advances in identifying and treating vulnerable plaques, the mortality rate and disability caused by such lesions remains the number one health threat in developed countries. Vulnerable, unstable plaques are characterized by a large necrotic core, implying a prominent role for necrotic cell death in atherosclerosis and plaque destabilization. Necrosis can occur accidentally or can be induced by tightly regulated pathways. Over the past decades, different forms of regulated necrosis, including necroptosis, ferroptosis, pyroptosis, and secondary necrosis, have been identified, and these may play an important role during atherogenesis. In this review, we describe several forms of necrosis that may occur in atherosclerosis and how pharmacological modulation of these pathways can stabilize vulnerable plaques. Moreover, some challenges of targeting necrosis in atherosclerosis such as the presence of multiple death-inducing stimuli in plaques and extensive cross-talk between necrosis pathways are discussed. A better understanding of the role of (regulated) necrosis in atherosclerosis and the mechanisms contributing to plaque destabilization may open doors to novel pharmacological strategies and will enable clinicians to tackle the residual cardiovascular risk that remains in many atherosclerosis patients.

Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review.

Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.