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Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis

Li, Wei; Sultana, Nargis; Siraj, Nabeel; Ward, Liam J.; Pawlik, Monika; Levy, Efrat; Jovinge, Stefan LU ; Bengtsson, Eva LU and Yuan, Xi Ming (2016) In Journal of Cellular and Molecular Medicine 20(9). p.1664-1672
Abstract

Autophagy dysfunction in mouse atherosclerosis models has been associated with increased lipid accumulation, apoptosis and inflammation. Expression of cystatin C (CysC) is decreased in human atheroma, and CysC deficiency enhances atherosclerosis in mice. Here, we first investigated the association of autophagy and CysC expression levels with atheroma plaque severity in human atherosclerotic lesions. We found that autophagy proteins Atg5 and LC3β in advanced human carotid atherosclerotic lesions are decreased, while markers of dysfunctional autophagy p62/SQSTM1 and ubiquitin are increased together with elevated levels of lipid accumulation and apoptosis. The expressions of LC3β and Atg5 were positively associated with CysC expression.... (More)

Autophagy dysfunction in mouse atherosclerosis models has been associated with increased lipid accumulation, apoptosis and inflammation. Expression of cystatin C (CysC) is decreased in human atheroma, and CysC deficiency enhances atherosclerosis in mice. Here, we first investigated the association of autophagy and CysC expression levels with atheroma plaque severity in human atherosclerotic lesions. We found that autophagy proteins Atg5 and LC3β in advanced human carotid atherosclerotic lesions are decreased, while markers of dysfunctional autophagy p62/SQSTM1 and ubiquitin are increased together with elevated levels of lipid accumulation and apoptosis. The expressions of LC3β and Atg5 were positively associated with CysC expression. Second, we investigated whether CysC expression is involved in autophagy in atherosclerotic apoE-deficient mice, demonstrating that CysC deficiency (CysC-/-) in these mice results in reduction of Atg5 and LC3β levels and induction of apoptosis. Third, macrophages isolated from CysC-/- mice displayed increased levels of p62/SQSTM1 and higher sensitivity to 7-oxysterol-mediated lysosomal membrane destabilization and apoptosis. Finally, CysC treatment minimized oxysterol-mediated cellular lipid accumulation. We conclude that autophagy dysfunction is a characteristic of advanced human atherosclerotic lesions and is associated with reduced levels of CysC. The deficiency of CysC causes autophagy dysfunction and apoptosis in macrophages and apoE-deficient mice. The results indicate that CysC plays an important regulatory role in combating cell death via the autophagic pathway in atherosclerosis. Copyright

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autophagy, Cystatin C, Lysosomal membrane permeabilization, Macrophage cell death
in
Journal of Cellular and Molecular Medicine
volume
20
issue
9
pages
9 pages
publisher
Wiley-Blackwell
external identifiers
  • Scopus:84963546295
  • Scopus:84982313662
  • WOS:000383586900006
ISSN
1582-1838
DOI
10.1111/jcmm.12859
language
English
LU publication?
yes
id
104a7eb4-8ef2-4bda-876d-178c44d51e72
date added to LUP
2016-09-21 12:09:51
date last changed
2017-01-08 05:59:15
@article{104a7eb4-8ef2-4bda-876d-178c44d51e72,
  abstract     = {<p>Autophagy dysfunction in mouse atherosclerosis models has been associated with increased lipid accumulation, apoptosis and inflammation. Expression of cystatin C (CysC) is decreased in human atheroma, and CysC deficiency enhances atherosclerosis in mice. Here, we first investigated the association of autophagy and CysC expression levels with atheroma plaque severity in human atherosclerotic lesions. We found that autophagy proteins Atg5 and LC3β in advanced human carotid atherosclerotic lesions are decreased, while markers of dysfunctional autophagy p62/SQSTM1 and ubiquitin are increased together with elevated levels of lipid accumulation and apoptosis. The expressions of LC3β and Atg5 were positively associated with CysC expression. Second, we investigated whether CysC expression is involved in autophagy in atherosclerotic apoE-deficient mice, demonstrating that CysC deficiency (CysC<sup>-/-</sup>) in these mice results in reduction of Atg5 and LC3β levels and induction of apoptosis. Third, macrophages isolated from CysC<sup>-/-</sup> mice displayed increased levels of p62/SQSTM1 and higher sensitivity to 7-oxysterol-mediated lysosomal membrane destabilization and apoptosis. Finally, CysC treatment minimized oxysterol-mediated cellular lipid accumulation. We conclude that autophagy dysfunction is a characteristic of advanced human atherosclerotic lesions and is associated with reduced levels of CysC. The deficiency of CysC causes autophagy dysfunction and apoptosis in macrophages and apoE-deficient mice. The results indicate that CysC plays an important regulatory role in combating cell death via the autophagic pathway in atherosclerosis. Copyright</p>},
  author       = {Li, Wei and Sultana, Nargis and Siraj, Nabeel and Ward, Liam J. and Pawlik, Monika and Levy, Efrat and Jovinge, Stefan and Bengtsson, Eva and Yuan, Xi Ming},
  issn         = {1582-1838},
  keyword      = {Autophagy,Cystatin C,Lysosomal membrane permeabilization,Macrophage cell death},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1664--1672},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Cellular and Molecular Medicine},
  title        = {Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis},
  url          = {http://dx.doi.org/10.1111/jcmm.12859},
  volume       = {20},
  year         = {2016},
}