title: Cell death-mediated cleavage of the attraction signal p43 in human atherosclerosis: implications for plaque destabilization.
abstract: OBJECTIVE
  Apoptosis is a key feature of advanced atherosclerotic plaques. Attraction signals such as p43 released from apoptotic cells play a crucial role in the timely removal of the apoptotic remnants by recruiting fresh phagocytes. Here, we sought to determine whether p43 may link apoptosis to inflammation and plaque progression.
  
  
  RESULTS
  RT-PCR and immunohistochemistry showed that p43 was abundantly expressed in human plaques compared with nonatherosclerotic mammary arteries and colocalized with splicing factor SC-35. Cell culture experiments indicated that p43 expression was associated with enhanced protein translation. On initiation of apoptosis or necrosis, p43 was cleaved by calpains and released as truncated protein p43(apoptosis-released factor [ARF]). Processing of p43 into endothelial monocyte activating polypeptide II was not observed. Full-length p43, but not p43(ARF) or endothelial monocyte activating polypeptide II, activated THP1 monocytes (upregulation of tumor necrosis factor alpha, interleukin 1 beta, interleukin 8, macrophage inflammatory protein (MIP)-1 alpha, MIP1 beta, MIP2 alpha) and endothelial cells (enhanced synthesis of E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tissue factor). The chemotactic activity of p43 or fragments thereof was poor compared with ATP. Treatment of smooth muscle cells with p43 did not induce cell death.
  
  
  CONCLUSIONS
  p43 is cleaved during apoptosis by calpains and released as a truncated protein that is harmless for the structure of the plaque.
authors.affiliation: Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. wim.martinet@ua.ac.be
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.forename: Inge
authors.initials: I
authors.lastname: De Meyer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cools
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.forename: Johan
authors.initials: J
authors.lastname: Bosmans
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C077219:small inducible cytokine subfamily E, member 1; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D002154:Calpain