title: Activation of the proapoptotic unfolded protein response in plaques of the human carotid artery.
abstract: OBJECTIVE
  To analyze expression of keystone markers of apoptosis and the proapoptotic signaling pathway "unfolded protein response" (UPR) in rupture-prone plaques of the human carotid artery.
  
  
  METHODS
  Plaque specimens were obtained during endarterectomy for high-grade carotid stenosis, and were formalin-fixed. Ten specimens were identified that exhibited criteria of advanced rupture-prone atherosclerotic plaques, and histological and immunohistological analysis of markers of apoptosis (cleaved Caspase-3, TUNEL) and UPR (KDEL, ATF3, CHOP, CHAC-1) was performed. In addition, co-localization of apoptosis and UPR-activation was assessed by double-immunohistochemistry.
  
  
  RESULTS
  The mean size of the necrotic core was 44 ± 7% and the mean minimum/representative thicknesses of the fibrous cap were 129 ± 39 μm/280 ± 60 μm, respectively. Each specimen fulfilled at least two of the criteria for rupture-prone plaques. Semi-quantitative analysis of immunohistochemistry showed a significant increase in cleaved Caspase-3-positive (1923 ± 93 cells/mm(2)) and TUNEL-positive cells (1387 ± 66 cells/mm(2)) when compared with control tissue. Furthermore, expression of UPR-markers KDEL, AFT3 and CHOP was significantly increased (1175 ± 40 cells/mm(2), 1971 ± 69 cells/mm(2) and 2173 ± 120 cells/mm(2), respectively). Co-localization of UPR-activation with apoptosis was confirmed by double-immunohistochemistry, and lesional macrophages were identified as the primary cell-type involved.
  
  
  CONCLUSIONS
  For the first time, activation of the proapoptotic signaling pathway UPR has been identified in advanced rupture-prone plaques of the human carotid artery. This provides additional evidence for adding UPR to the potential targets for controlling plaque apoptosis and thereby preventing plaque progression/rupture.
authors: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany. Electronic address: bernhard.dorweiler@unimedizin-mainz.de.
authors: B
authors: B
authors: Dorweiler
authors: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
authors: I
authors: I
authors: Grechowa
authors: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
authors: A
authors: A
authors: Wallrath
authors: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
authors: C F
authors: CF
authors: Vahl
authors: Center for Thrombosis and Hemostasis, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
authors: S
authors: S
authors: Horke
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D016894:Endarterectomy, Carotid; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018000:Receptors, Peptide / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D015415:Biomarkers; C064459:KDEL receptor; D018000:Receptors, Peptide; D051742:Transcription Factor CHOP; D053148:Caspase 3
keywords: Apoptosis; Atherosclerotic plaque; Carotid stenosis; Immunohistochemistry; Unfolded protein response