Free Cholesterol Loading of Macrophages Induces Apoptosis Involving the Fas Pathway

Yao, Pin Mei; Tabas, Ira

doi:10.1074/jbc.m002087200

Cited by 170 publications

(178 citation statements)

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“…Indeed, FasL localizes to apoptotic SMC in advanced lesions and induces apoptosis of SMC in vitro (21,22). In addition, the cellular effectors of immune-mediated apoptosis in atherosclerotic plaques are likely T cells and macrophages, as these leukocytes have been implicated in SMC apoptosis and in the development of acute coronary syndromes (8,(23)(24)(25)(26)(27). Our association of granzyme B immunoreactivity with advanced atherosclerotic disease, and localization of granzyme B to apoptotic cells, suggests that this cytotoxic immune factor may further contribute to acute coronary syndromes through a similar mechanism as FasL.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

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Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD).Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle ␣-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0 -5؉/5؉ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle ␣-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.

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Section: Discussionmentioning

confidence: 99%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

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“…By using cultured macrophages incubated with a source of lipoprotein cholesterol (acetylated low-density lipoprotein) and an acylCoA:cholesterol acyltransferase inhibitor to block cholesterol esterification, we have shown that apoptotic death of FC-loaded cultured macrophages is caused by both activation of Fas ligand and release of cytochrome c from mitochondria (17,18). Most interestingly, FC-induced apoptosis in macrophages is entirely dependent on cholesterol trafficking to the endoplasmic reticulum (ER) (22).…”

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confidence: 99%

“…An important cytotoxic condition that deserves attention is excess cellular free cholesterol (FC) (9). FC accumulation in lesional foam cells has been well documented (10)(11)(12)(13)(14), and studies with cultured macrophages have shown that excess cellular FC is a potent inducer of cell death (15)(16)(17)(18).…”

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confidence: 99%

Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

Feng

Zhang

Kuriakose

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and likely promotes plaque instability, a precursor of acute vascular events. Macrophages in advanced lesions accumulate large amounts of unesterified cholesterol, which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires cholesterol trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from mice with a heterozygous mutation in the cholesterol-trafficking protein Npc1 have a selective defect in cholesterol trafficking to the ER and are protected from cholesterol-induced apoptosis. The goal of the present study was to test the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in Npc1 ؉/؉ ;Apoe ؊/؊ and Npc1 ؉/؊ ;Apoe ؊/؊ mice. Although advanced lesions in Npc1 ؉/؉ ;Apoe ؊/؊ mice had extensive acellular areas that were rich in unesterified cholesterol and macrophage debris, the lesions of Npc1 ؉/؊ ;Apoe ؊/؊ mice were substantially more cellular and less necrotic. Moreover, compared with Npc1 ؉/؊ ;Apoe ؊/؊ lesions, Npc1 ؉/؉ ;Apoe ؊/؊ lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)-positive areas surrounding necrotic areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of mice. These data provide in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ERbased model of cholesterol-induced cytotoxicity is physiologically relevant. Moreover, by showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.

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“…With continued FC loading, however, these adaptive mechanisms fail, and the cells develop the molecular and morphological properties of apoptosis and necrosis (8,9). In particular, Fas ligand is activated; Bax levels increase; mitochondrial membrane potential drops; mitochondrial cytochrome c is released into the cytoplasm; and proximal and distal caspases are activated (21,22). Cell death ensues, with the majority of macrophages showing the morphological signs of apoptosis initially, followed by typical necrotic properties after very long period of FC loading (8,9).…”

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confidence: 99%

ABCA1-mediated Cholesterol Efflux Is Defective in Free Cholesterol-loaded Macrophages

Feng¹,

Tabas

2002

Journal of Biological Chemistry

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135

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In advanced atherosclerosis, macrophage foam cells progressively accumulate large amounts of unesterified or "free" cholesterol (FC), a process that is thought to contribute to foam cell death and lesional necrosis. The cellular consequences of early FC accumulation, including those that lead to further FC accumulation, are poorly understood. In this context, we show that cholesterol and phospholipid efflux mediated by ABCA1, which is initially induced in the cholesterol-loaded macrophage, was inhibited by ϳ80% in pre-toxic FCloaded macrophages. Cholesterol efflux to HDL 2 , which is mediated by a non-ABCA1 pathway, was inhibited by only ϳ20% in FC-loaded macrophages. FC loading led to decreased levels of ABCA1 protein via increased degradation of ABCA1, and not by decreased transcription or translation of AbcA1 mRNA. The decrease in ABCA1 protein occurred relatively early and was not prevented by caspase inhibitors, indicating that it was not a consequence of FC-induced apoptosis. However, inhibition of proteasomal function by lactacystin largely prevented the degradation of ABCA1. Importantly, the FC-induced decrease in ABCA1 function and protein was almost entirely prevented in macrophages that had partial deficiency of npc1 or were exposed to nanomolar concentrations of U18666A, both of which lead to defective cholesterol trafficking to the endoplasmic reticulum, but leave trafficking to the plasma membrane largely intact. Thus, a relatively early event during FC loading of macrophages is increased degradation of ABCA1, which appears to require trafficking of cholesterol to a peripheral cellular site, but not bulk trafficking of excess cholesterol to the plasma membrane. These findings provide new insight into the post-translational regulation of ABCA1 and the pathobiology of the FC-loaded macrophage.

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Free Cholesterol Loading of Macrophages Induces Apoptosis Involving the Fas Pathway

Cited by 170 publications

References 54 publications

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

ABCA1-mediated Cholesterol Efflux Is Defective in Free Cholesterol-loaded Macrophages

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