Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage

Abstract

Background-Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. Methods and Results-We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes. Conclusions-Considered together, our data suggest that macrophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ inflammation Ⅲ leukocytes Ⅲ macrophages Ⅲ pathology Ⅲ survival A therosclerosis is an inflammatory vascular disease characterized by the intimal accumulation of macrophage foam cells, cell death, and chronic arterial inflammation. 1 Macrophage apoptosis has been identified as a prominent feature of atherosclerotic plaques because macrophage cell death is believed to support necrotic core growth. The apoptotic process is controlled by intracellular levels of proapoptotic and antiapoptotic proteins such as those of the Bcl-2 family. Indeed, the relative expression of proapoptotic (eg, Bax and Bak) and antiapoptotic proteins (eg, Bcl-2 and Bcl-xL) of the Bcl-2 family determines the overall sensitivity of the cell to apoptotic stimuli. In macrophages of atherosclerotic lesions, the proapoptotic Bax and Bak proteins predominate, whereas the antiapoptotic Bcl-2 and Bcl-xL are deficient, 2,3 thereby arguing for their enhanced susceptibility to apoptosis. However, the impact of macrophage apoptosis on plaque progression remains to be specifically investigated. Clinical Perspective p 1804Recent studies have shed light on the potential impact of apoptosis on atherosclerotic lesion progression. Indeed, disruption of either the proapoptotic molecule Bax in bone marrow-derived cells 4 or the antiapoptotic factor AIM 5 has revealed that apoptosis attenuates early plaque formation.However, because apoptotic cells accumulate preferentially in advanced rather than in early lesions, 6,7 macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. 8 In addition, apoptotic cell clearance appears to be defective in advanced lesions but efficient in early ones. 9 Moreover, apoptotic cells may possess proinflammatory properties, in part as a result of t...

The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages

“…35 Therefore, the antiapoptosis effects of macrophages in early-stage atherosclerotic lesions increase the likelihood of plaque development. 34 Our group previously confirmed that PpIX could enter athermanous plaques in the rabbit carotid artery. 5 We found that PpIX mainly targeted and accumulated in metabolically active inflammatory macrophages in the athermanous plaques of ApoE -/-mice (data not shown).…”

“…33 Moreover, macrophages play a crucial role in the progression and instability of atherosclerotic plaques. [34][35][36] Thus, promoting the clearance of macrophages from plaques is an alternative strategy for treating AS. SDT, which combines low-intensity ultrasound with different sonosensitizers, has been demonstrated to induce apoptosis in a variety of cell types relevant to different diseases.…”

The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis

“…For infl ammation studies, cells were treated with 10 or 100 ng/ml LPS (Axxora, macrophage (AIM) decreased lesion formation in bone marrow transplantation experiments owing to an increase in macrophage apoptosis ( 25,26 ). In this setting, apoptotic cell death of foam cells at the initial stages of atherosclerosis was associated with decreased lesion progression ( 27,28 ).…”

Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression

“…Furthermore, the 9p21 genetic locus, which impacts proliferation of vascular cells, has been associated with susceptibility to coronary artery disease (17)(18)(19). With regard to survival, apoptosis of macrophages in the plaque is detected at all stages of the disease and is not proinflammatory in early, fatty streak lesions (20,21). Mutations in Cx3cr1 and Csf1 accelerate loss of macrophages from plaques, at least in part through increased apoptosis (2,22).…”

“…As a consequence of decreased efferocytosis, apoptosis leads to secondary necrosis. In this setting, accumulation of dead cell debris amplifies proinflammatory signals and triggers further monocyte recruitment (20).…”