title: Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis.
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. 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.
authors.affiliation: Division of Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Occupational and Environmental Medicine Center, Heart and Medicine Center, County Council of Östergötland, Linköping, Sweden.
authors.forename: Nargis
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Occupational and Environmental Medicine Center, Heart and Medicine Center, County Council of Östergötland, Linköping, Sweden.|Department of internal medicine, University of Alberta Edmonton, Alberta, Canada.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Siraj
authors.affiliation: Division of Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.|Occupational and Environmental Medicine Center, Heart and Medicine Center, County Council of Östergötland, Linköping, Sweden.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Ward
authors.affiliation: Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Pawlik
authors.affiliation: Nathan S. Kline Institute for Psychiatric Research, Departments of Psychiatry and Biochemistry and Molecular Pharmacology, New York University Langone School of Medicine, New York, NY, USA.
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jovinge
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Bengtsson
authors.affiliation: Occupational and Environmental Medicine Center, Heart and Medicine Center, County Council of Östergötland, Linköping, Sweden.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D055316:Cystatin C / Q000172:deficiency / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D010539:Permeability; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D055316:Cystatin C; D011994:Recombinant Proteins
keywords: autophagy; cystatin C; lysosomal membrane permeabilization; macrophage cell death