Expression of Bcl‐x, Bcl‐2, Bax, and Bak in endarterectomy and atherectomy specimens

Saxena, Anurag; McMeekin, James; Thomson, Dorothy

doi:10.1002/path.1040

Cited by 40 publications

(37 citation statements)

References 63 publications

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“…The alteration in the expression of Bcl-2 family protein appeared to be related to apoptosis of VSMCs in atherosclerosis. In the apoptotic cells of endarterectomy and atherectomy specimens, there was increased expression of pro-apoptotic Bax and Bak coupled with a paucity of Bcl-2 and lack of Bcl-X L [25]. Bax induced cyt c release from mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of TNF‐α‐mediated cell death in vascular smooth muscle cells through cytochrome c‐independent pathway by the proteasome inhibitor

Kim

2003

FEBS Letters

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There is substantial evidence that cytokines induce apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerosis. Its regulation, however, is not completely de¢ned. The aim of this study is to investigate whether proteasome activity is related with apoptosis in VSMCs by tumor necrosis factor-K K (TNF-K K). Rat aorta smooth muscle cells were treated with TNF-K K and proteasome inhibitor MG132 and then cell death was determined by morphology, viability, and DNA fragmentation. MG132 or TNF-K K alone did not induce cell death. In contrast, co-treatment of TNF-K K and proteasome inhibitor induced death and DNA degradation in VSMCs, suggesting proteasome inhibitor enhanced death activity of TNF-K K. The death was not blocked by ascorbic acid but by nitric oxide synthase inhibitor N G -monomethyl-L-arginine. Both caspase-3 and -8 were activated during the death by the proteasome inhibitor and TNF-K K. The death was e¡ectively blocked by the caspase-3 inhibitor z-DEVD-fmk, suggesting a role of caspase-3 in the death. Nonetheless, there were no signi¢cant alterations in the level of Bcl-2, Bcl-X L , Bax and Bak by the proteasome inhibitor, nor any evidence of cytochrome (cyt) c release into cytosol from dying cells, suggesting that cyt c is not involved. These results suggest that proteasome inhibition potentiates TNFmediated death in VSMCs in a cyt c-independent pathway. The present study proposes a new mechanism by which VSMCs undergo death by cytokines. ß

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Section: Discussionmentioning

confidence: 99%

Enhancement of TNF‐α‐mediated cell death in vascular smooth muscle cells through cytochrome c‐independent pathway by the proteasome inhibitor

Kim

2003

FEBS Letters

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“…Apoptosis has been closely associated with atherosclerosis because a higher apoptotic index has been observed in advanced atherosclerotic lesions compared with early ones (29,30,48). In the later stages of atherogenesis, up-regulated apoptosis in combination with impaired, cytoprotective autophagy in SMCs within the thin fibrous cap of lesions can promote plaque rupture, thrombosis, and subsequent myocardial infarction and stroke (1,3,4).…”

Section: Discussionmentioning

confidence: 99%

“…In a rabbit atherosclerotic model, increased levels of Bcl-X L , an anti-apoptotic member of the Bcl-2 family, have been found in the intima of early proliferative lesions and the down-regulation of Bcl-X L in neointima resulted in apoptosis of vascular cells and the regression of lesions (29). Likewise, higher Bcl-X L levels were observed in apoptosis-resistant cells of human advanced lesions compared with control specimens, and had a protective effect against apoptotic insults (30). Moreover, our prior work in transcript profiling of lesion-derived cell (LDC) apoptosis revealed that up-regulated expression of Bcl-X L is a major determinant of resistance to Fas-mediated apoptosis (31,32).…”

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confidence: 87%

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

Zhaorigetu

Yang

Toma

et al. 2011

Journal of Biological Chemistry

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Inflammatory cytokine-regulated apoptosis and autophagy play pivotal roles in plaque rupture and thrombosis of atherosclerotic lesions. However, the molecular interplay between apoptosis and autophagy in vascular cells has not been investigated. Our prior study showed that human apolipoprotein L6 (ApoL6), a pro-apoptotic BH3-only member of the Bcl-2 family, was one of the downstream targets of interferon-␥ (INF␥), which sensitizes atherosclerotic lesion-derived cells (LDCs) to Fas-induced apoptosis. To investigate whether ApoL6 plays a causal role in atherosclerotic apoptosis and autophagy, in this study, we demonstrate that IFN␥ treatment itself strongly induces ApoL6, and ApoL6 is highly expressed and partially colocalized with activated caspase 3 in activated smooth muscle cells in atherosclerotic lesions. In addition, overexpression of ApoL6 promotes reactive oxygen species (ROS) generation, caspase activation, and subsequent apoptosis, which can be blocked by pan caspase inhibitor and ROS scavenger. Knockdown of ApoL6 expression by siApoL6 suppresses INF␥-and Fas-mediated apoptosis. Further, ApoL6 binds Bcl-X L , one of the most abundant anti-death proteins in LDCs. Interestingly, forced ApoL6 expression in LDCs induces degradation of Beclin 1, accumulation of p62, and subsequent attenuation of LC3-II formation and translocation and thus autophagy, whereas siApoL6 treatment reverts the phenotype. Taken together, our results suggest that ApoL6 regulates both apoptosis and autophagy in SMCs. IFN␥-initiated, ApoL6-induced apoptosis in vascular cells may be an important factor causing plaque instability and a potential therapeutic target for treating atherosclerosis and cardiovascular disease.Atherosclerosis, a chronic inflammatory disease and the principal cause of heart attack and stroke, contributes to at least 30% of all mortality in the United States (1, 2). The atherosclerotic lesion results from a dynamic interplay involving many elements of dysfunctional wound repair, including proliferation, matrix synthesis, autophagy (self-eating), and apoptosis, in response to insult of the vascular endothelial cells (ECs) 2 and smooth muscle cells (SMCs) of the artery wall (3, 4). The crosstalk between cytokines, chemokines, growth factors, oxidized lipid species/low density lipoproteins (LDLs), and reactive oxygen species (ROS) in atherosclerotic lesions determine cell survival and death (5, 6). Inflammation, based on the particular cellular context, can modulate proliferation or apoptosis (type I programmed cell death) of different cell-types, such as ECs, SMCs, and the inflammatory infiltrate (lymphocytes, and monocytes/macrophages) in atherosclerotic lesions (7,8). With regard to cell death, it has been well documented that during the early stages of lesion development, apoptosis of macrophages contributes to the accumulation of extracellular LDLs and protein debris, while in the later stages, activated SMCs encapsulate the lipid-rich regions, and their persistence contributes to collagen synthesis, matrix accu...

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“…10 -12 Atherosclerotic plaque apoptosis 6,8 is associated with predominant caspase-3 activation in SMCs 13 and macrophages. 7,12,14,15 Atherosclerotic SMCs and macrophages express pro-apoptotic regulators of mitochondrial integrity Bax and Bad, but they lack cytoprotective Bcl-xL and Bcl-2, 16,17 resulting in defective mitochondrial integrity and apoptosis. Moreover, the endogenous caspase inhibitor, cellular inhibitor of apoptosis (IAP) protein-2 (cIAP2) is thought to be expressed in atherosclerotic endothelial cells, 18 but these cells are prone to apoptosis in atherosclerosis.…”

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confidence: 99%

IAP Survivin Regulates Atherosclerotic Macrophage Survival

Blanc‐Brude

Teissier

Castier

et al. 2007

ATVB

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Objectives-Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but its mechanisms remain enigmatic. We hypothesized that inhibitor of apoptosis protein (IAP) survivin regulates macrophage death in atherosclerosis. Methods and Results-Western blot analysis revealed discrete survivin expression in human aorta lipid streaks but virtually none in advanced atherosclerotic plaques, despite increased XIAP and cIAP2 levels. Survivin was detected in CD68-positive macrophages infiltrating human lipid streaks by immunohistochemistry. In advanced atherosclerotic plaques, only rare macrophages outside the necrotic core or occasional fibrous cap smooth muscle cells expressed survivin. In vitro, macrophage colony-stimulating factor-stimulated mouse macrophage survivin expression, proliferation and resistance to apoptosis. Conversely, prolonged oxidized low-density lipoprotein treatment abolished macrophage survivin expression and triggered apoptosis after 12 hours, despite enhanced XIAP and cIAP2 expression. Adenoviral overexpression of survivin conferred macrophages with sustained resistance to apoptosis after oxidized low-density lipoprotein, tumor necrosis factor-␣, or staurosporine challenge. Conclusions-Survivin is a critical modulator of atherosclerotic macrophage apoptosis under dual control by growth factors and oxidized lipids accumulating in atheroma. In early lipid streaks, growth factor-stimulated survivin expression may contribute to macrophage accumulation and survival, but dysregulation of survivin expression caused by recurrent oxidized low-density lipoprotein exposure may favor apoptosis in advanced atherosclerotic plaques, despite upregulated cIAP2 and XIAP.

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Expression of Bcl‐x, Bcl‐2, Bax, and Bak in endarterectomy and atherectomy specimens

Cited by 40 publications

References 63 publications

Enhancement of TNF‐α‐mediated cell death in vascular smooth muscle cells through cytochrome c‐independent pathway by the proteasome inhibitor

Enhancement of TNF‐α‐mediated cell death in vascular smooth muscle cells through cytochrome c‐independent pathway by the proteasome inhibitor

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

IAP Survivin Regulates Atherosclerotic Macrophage Survival

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