Journal of Vascular Research

Research Paper

Resistance to Fas-Induced Apoptosis in Cells from Human Atherosclerotic Lesions: Elevated Bcl-XL Inhibits Apoptosis and Caspase Activation

Yang Z.a · Gagarin D.a · Ramezani A.b · Hawley R.G.b · McCaffrey T.A.a

Author affiliations

aDepartment of Biochemistry and Molecular Biology, George Washington University Medical Center and bDepartment of Anatomy and Cell Biology, The Catherine Birch McCormick Genomics Center, Washington, D.C., USA

Keywords: Myocardial infarctionStrokeRestenosisAngioplastyBcl-XL BADSTAT6CaspaseFas

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J Vasc Res 2007;44:483–494
https://doi.org/10.1159/000106466

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Article / Publication Details

First-Page Preview
Abstract of Research Paper

Received: October 09, 2006
Accepted: May 09, 2007
Published online: July 26, 2007
Issue release date: October 2007

Number of Print Pages: 12
Number of Figures: 11
Number of Tables: 1

ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)

For additional information: https://www.karger.com/JVR

Abstract

The inappropriate survival of cells in the neointima contributes to atherosclerotic plaque progression, while apoptosis in the fibrous cap of lesions contributes to myocardial infarction and stroke. Prior genomic-scale transcript profiling of human carotid artery plaque cells with known sensitivity or resistance to fas-induced apoptosis identified candidate genes involved in lesion cell apoptosis. Retroviral overexpression indicated that several candidate factors were not causative, but that Bcl-XL conferred complete resistance to apoptosis induced by fas ligation. Resistant cells failed to efficiently activate caspase 8, an effect which was also observed in Bcl-XL-transfected cells. Small-molecule Bcl-2/XL inhibitors and siRNA knockdown of Bcl-XL markedly sensitized resistant cells to apoptosis, and partially restored caspase 8 activation. Caspase 3, 6 and 9 inhibitors reduced caspase 8 activation and blocked apoptosis. Complete knockdown of caspase 9 did not reduce apoptosis, while knockdown of Bid suppressed apoptosis, suggesting that mitochondrial pathways independent of caspase 9, such as Smac/Diablo or AIF, provide a necessary mitochondrial input to efficient caspase activation. Bcl-XL appears to modulate lesion cell apoptosis by suppressing mitochondrial amplification of caspase activation loops. The results may have direct implications for controlling plaque instability/progression, and identify a new class of small molecules to inhibit restenosis.

© 2007 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Research Paper

Received: October 09, 2006
Accepted: May 09, 2007
Published online: July 26, 2007
Issue release date: October 2007

Number of Print Pages: 12
Number of Figures: 11
Number of Tables: 1

ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)

For additional information: https://www.karger.com/JVR

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2007, Vol.44, No. 6

October 2007

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