Autophagy and Its Association with Macrophages in Clonal Hematopoiesis Leading to Atherosclerosis

Abstract

Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration, is linked to plaque formation and cardiovascular events. While traditionally associated with lipid metabolism and endothelial dysfunction, recent research highlights the roles of autophagy and clonal hematopoiesis (CH) in its pathogenesis. Autophagy, a cellular process crucial for degrading damaged components, regulates macrophage homeostasis and inflammation, both of which are pivotal in atherosclerosis. In macrophages, autophagy influences lipid metabolism, cytokine regulation, and oxidative stress, helping to prevent plaque instability. Defective autophagy exacerbates inflammation, impairs cholesterol efflux, and accelerates disease progression. Additionally, autophagic processes in endothelial cells and smooth muscle cells further contribute to atherosclerotic pathology. Recent studies also emphasize the interplay between autophagy and CH, wherein somatic mutations in genes like TET2, JAK2, and DNMT3A drive immune cell expansion and enhance inflammatory responses in atherosclerotic plaques. These mutations modify macrophage function, intensifying the inflammatory environment and accelerating atherosclerosis. Chaperone-mediated autophagy (CMA), a selective form of autophagy, also plays a critical role in regulating macrophage inflammation by degrading pro-inflammatory cytokines and oxidized low-density lipoprotein (ox-LDL). Impaired CMA activity leads to the accumulation of these substrates, activating the NLRP3 inflammasome and worsening inflammation. Preclinical studies suggest that pharmacologically activating CMA may mitigate atherosclerosis progression. In animal models, reduced CMA activity accelerates plaque instability and increases inflammation. This review highlights the importance of autophagic regulation in macrophages, focusing on its role in inflammation, plaque formation, and the contributions of CH. Building upon current advances, we propose a hypothesis in which autophagy, programmed cell death, and clonal hematopoiesis form a critical intrinsic axis that modulates the fundamental functions of macrophages, playing a complex role in the development of atherosclerosis. Understanding these mechanisms offers potential therapeutic strategies targeting autophagy and inflammation to reduce the burden of atherosclerotic cardiovascular disease.

Keywords: atherosclerosis; chaperone-mediated autophagy (CMA); clonal hematopoiesis (CH); inflammatory; macrophage; programmed cell death.

Figure 1

Signaling molecular pathways are altered from circumstance in a normal physiological artery (top) to that in an atherosclerotic artery (bottom) through chaperone-mediated autophagy, macrophage pyroptosis, and clonal hematopoiesis (middle) to atherosclerosis (AS). (A) Chaperone-mediated autophagy (CMA) is a selective autophagic process. (B) Dysfunction of autophagy affects macrophage lipid accumulation. (C) Autophagy mediates pyroptosis in macrophages. (D) Mutations in clonal hematopoiesis (CH) are the AS risk factors (figure not to scale).

Figure 2

Cellular and developmental mechanisms of macrophages in clonal hematopoiesis associated with atherosclerosis. This figure illustrates the various stem cell lineages involved in the development of macrophages during clonal hematopoiesis (CH) and their contributions to cardiovascular pathophysiology. Macrophages originating from these lineages play a significant role in cardiac fibrosis, heart failure, and overall cardiovascular function. These macrophages arise from hematopoietic stem cells (HSCs), which begin their development from yolk sac cells during the early embryonic stage [139]. Hematopoiesis continues through the embryonic liver and dorsal aorta, ultimately transitioning to bone marrow for sustained blood cell production. Pathological autophagy in these macrophages contributes to cardiovascular diseases, including cardiac fibrosis and coronary ischemia. In contrast, physiological autophagy, promoted by a healthy lifestyle, supports cardiac health and enhances cognitive function, potentially mitigating the effects of aging (figure not to scale).