title: ATG16L1 Expression in Carotid Atherosclerotic Plaques Is Associated With Plaque Vulnerability.
abstract: OBJECTIVE
  Autophagy has emerged as a cell survival mechanism critical for cellular homeostasis, which may play a protective role in atherosclerosis. ATG16L1, a protein essential for early stages of autophagy, has been implicated in the pathogenesis of Crohn's disease. However, it is unknown whether ATG16L1 is involved in atherosclerosis. Our aim was to analyze ATG16L1 expression in carotid atherosclerotic plaques in relation to markers of plaque vulnerability.
  
  
  RESULTS
  Histological analysis of 143 endarterectomized human carotid atherosclerotic plaques revealed that ATG16L1 was expressed in areas surrounding the necrotic core and the shoulder regions. Double immunofluorescence labeling revealed that ATG16L1 was abundantly expressed in phagocytic cells (CD68), endothelial cells (CD31), and mast cells (tryptase) in human advanced plaques. ATG16L1 immunogold labeling was predominantly observed in endothelial cells and foamy smooth muscle cells of the plaques. ATG16L1 protein expression correlated with plaque content of proinflammatory cytokines and matrix metalloproteinases. Analysis of Atg16L1 at 2 distinct stages of the atherothrombotic process in a murine model of plaque vulnerability by incomplete ligation and cuff placement in carotid arteries of apolipoprotein-E-deficient mice revealed a strong colocalization of Atg16L1 and smooth muscle cells only in early atherosclerotic lesions. An increase in ATG16L1 expression and autophagy flux was observed during foam cell formation in human macrophages using oxidized-LDL.
  
  
  CONCLUSIONS
  Taken together, this study shows that ATG16L1 protein expression is associated with foam cell formation and inflamed plaque phenotype and could contribute to the development of plaque vulnerability at earlier stages of the atherogenic process.
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.). joelle.magne@ki.se.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Magné
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Peter
authors.initials: P
authors.lastname: Gustafsson
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves
authors.affiliation: From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (J.M., P.G., H.J., L.M., P.E., E.E.), Division of Clinical Research Center, Department of Laboratory Medicine (K.H.), Division of Renal Medicine, Department of Clinical Science, Technology and Intervention (A.W.), Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Wihuri Research Institute, Helsinki, Finland (P.T.K.); and Experimental Cardiovascular Research Group and Cardiology Department, Skåne University Hospital, Clinical Research Center, Clinical Sciences Malmö, Lund University, Sweden (I.G.).
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D016893:Carotid Stenosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D016894:Endarterectomy, Carotid / Q000379:methods; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005487:Foam Cells / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000502:physiology; D018570:Risk Assessment; D012494:Sampling Studies; D012680:Sensitivity and Specificity
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins
keywords: ATG16L1; atherosclerosis; autophagy; carotid plaque