Macrophage pyroptosis in atherosclerosis: therapeutic potential

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease characterized by the accumulation of lipid-rich plaques in arterial walls, leading to cardiovascular events such as myocardial infarction and stroke. Macrophage pyroptosis, a form of programmed cell death driven by the NLRP3 inflammasome and caspase-1 activation, plays a critical role in the progression and destabilization of atherosclerotic plaques. This review explores the molecular mechanisms underlying macrophage pyroptosis and their significant contributions to AS pathogenesis. Recent advancements have highlighted the therapeutic potential of targeting key components of the pyroptotic pathway, including the use of nanotechnology to increase drug delivery specificity. These strategies are promising for reducing inflammation, stabilizing plaques, and mitigating the clinical impact of AS. Future studies should focus on translating these findings into clinical applications to develop effective treatments that can halt or reverse AS progression by modulating macrophage pyroptosis.

1. Introduction

Atherosclerosis (AS) is a chronic, progressive inflammatory disease of the medium and large arteries characterized by the accumulation of lipid-rich foam cells and fibrous tissues within the intima of the elastic arteries. This accumulation can lead to the development of plaques and serious complications, such as myocardial infarction and stroke [1]. Many risk factors, such as age, smoking, unhealthy diet, and dyslipidemia, have been identified as contributing factors to the incidence of AS [2]. AS progression is characterized by dysregulated programmed death of plaque cells, including vascular endothelial cells (VECs), macrophages, and vascular smooth muscle cells (VSMCs), which exacerbates inflammatory responses [3,4].

In the early stages of AS, oxidized low-density lipoprotein (ox-LDL) induces injury, activation, and death in VECs, facilitating the recruitment of monocytes and other circulating leukocytes for transendothelial migration. Within the endothelium, monocytes differentiate into macrophages, which become foam cells upon engulfment of excess lipids [5]. Additionally, VEC death promotes the proliferation and migration of adjacent VSMCs into the arterial intima, enhancing the synthesis of extracellular matrix components and thereby contributing to plaque formation and impairing vasodilatory functions [6]. Although macrophage death may initially help suppress inflammation in early atherosclerotic lesions, it significantly accelerates disease progression in the advanced stages of AS [7]. The inadequate clearance of dying macrophages within vessel walls leads to the release of intracellular pro-inflammatory cytokines and lipids into the extracellular space, driving necrotic core formation and contributing to plaque instability [7,8]. These studies suggest that macrophage death is a critical factor in AS progression.