title: Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?
abstract: OBJECTIVE
  Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk.
  
  
  RESULTS
  We studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P (P < 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen (P < 0.01) but much lower in the area close to NC (P < 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk (P < 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium (P < 0.01). This effect of TANC extract was most evoked by its content in F(2)-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids.
  
  
  CONCLUSIONS
  Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis.
authors.affiliation: Department of Medicine, Section of Internal Medicine D,  University of Verona, Verona 37121,  Italy.
authors.forename: Ulisse
authors.initials: U
authors.lastname: Garbin
authors.forename: Elda
authors.initials: E
authors.lastname: Baggio
authors.forename: Chiara
authors.initials: C
authors.lastname: Stranieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Pasini
authors.forename: Stefania
authors.initials: S
authors.lastname: Manfro
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzini
authors.forename: Paola
authors.initials: P
authors.lastname: Vallerio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lipari
authors.forename: Flavia
authors.initials: F
authors.lastname: Merigo
authors.forename: Giancesare
authors.initials: G
authors.lastname: Guidi
authors.forename: Luciano
authors.initials: L
authors.lastname: Cominacini
authors.forename: Anna
authors.initials: A
authors.lastname: Fratta Pasini
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000368:Aged; D017209:Apoptosis; D002339:Carotid Arteries / Q000201:enzymology* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D028441:F2-Isoprostanes / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D009336:Necrosis; D010084:Oxidation-Reduction; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014162:Transfection; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D028441:F2-Isoprostanes; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D036341:Intercellular Signaling Peptides and Proteins; D044243:Linoleic Acids, Conjugated; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C024347:9-hydroxy-10,12-octadecadienoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C097072:MERTK protein, human; C000606462:ADAM17 protein, human