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Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis
Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Department of internal medicine, University of Alberta Edmonton, Alberta, Canada.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
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2016 (English)In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 20, no 9, 1664-1672 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016. Vol. 20, no 9, 1664-1672 p.
Keyword [en]
autophagy, cystatin C, macrophage cell death, lysosomal membrane permeabilization
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-132541DOI: 10.1111/jcmm.12859ISI: 000383586900006PubMedID: 27079462OAI: oai:DiVA.org:liu-132541DiVA: diva2:1046367
Note

Funding Agencies|Swedish Heart Lung Foundation; Torsten and Ragnar Soderbergs Foundation; Stroke Foundation; Olle Engkvist Foundation; Swedish Gamla Tjanarinnor Foundation; Linkoping University; Linkoping University Hospital Research Foundation; Magnus Bergvall Foundation; Syskonen Svensson Foundation; Crafoord Foundation; Royal Physiographic Society; Lars Hierta Foundation; Lundstrom Foundation; Malmo University Hospital Foundation; Swedish Society of Medicine; USA National Institutes of Health

Available from: 2016-11-14 Created: 2016-11-13 Last updated: 2016-12-05Bibliographically approved

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Li, WeiSultana, NargisWard, LiamYuan, Ximing
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Department of Gynaecology and Obstetrics in LinköpingDepartment of Clinical and Experimental MedicineFaculty of Medicine and Health SciencesOccupational and Environmental Medicine CenterDivision of Clinical SciencesDivision of Neuro and Inflammation Science
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