title: Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.
abstract: OBJECTIVE
  Increasing evidence suggests that chronic inflammation contributes to atherogenesis, and that acute inflammatory events cause plaque rupture, thrombosis, and myocardial infarction. The present studies examined how inflammatory factors, such as interferon-gamma (IFNgamma), cause increased sensitivity to apoptosis in vascular lesion cells.
  
  
  RESULTS
  Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-gamma (IFNgamma) to Fas-induced apoptosis, in a Bcl-X(L) reversible manner. Microarray profiling identified 72 INFgamma-induced transcripts with potential relevance to apoptosis. Half could be excluded because they were induced by IRF-1 overexpression, which did not sensitize to apoptosis. IFNgamma treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-X(L) (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFNgamma-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFNgamma-induced sensitivity to Fas ligation and prevented Fas/IFNgamma-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-X(L). Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-X(L) levels after IFNgamma treatment.
  
  
  CONCLUSIONS
  Although critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis and may thus be an important factor in plaque rupture and myocardial infarction.
authors.affiliation: The George Washington Medical Center, Department of Biochemistry and Molecular Biology, 2300 I Street NW, Ross Hall 541, Washington, DC 20037, USA.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Yang
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gagarin
authors.forename: Georges
authors.initials: G
authors.lastname: St Laurent
authors.forename: Neil
authors.initials: N
authors.lastname: Hammell
authors.forename: Ian
authors.initials: I
authors.lastname: Toma
authors.forename: Chien-An
authors.initials: CA
authors.lastname: Hu
authors.forename: Ayaka
authors.initials: A
authors.lastname: Iwasa
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McCaffrey
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051020:bcl-X Protein; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex