Cardiovascular inflammation and lesion cell apoptosis: A novel connection via the interferon-inducible immunoproteasome
Arteriosclerosis, Thrombosis, and Vascular Biology
Apoptosis; Fas; Immunoproteasome; Inflammation; Interferon; LMP7; Mcl-1; PSMB8
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-γ (IFNγ), cause increased sensitivity to apoptosis in vascular lesion cells. METHODS AND RESULTS-: Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-γ (IFNγ) to Fas-induced apoptosis, in a Bcl-XL reversible manner. Microarray profiling identified 72 INFγ-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. IFNγ treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-XL (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFNγ-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ 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. © 2009 American Heart Association, Inc.
Yang, Z., Gagarin, D., St. Laurent, G., Hammell, N., Toma, I., Hu, C., Iwasa, A., & McCaffrey, T. (2009). Cardiovascular inflammation and lesion cell apoptosis: A novel connection via the interferon-inducible immunoproteasome. Arteriosclerosis, Thrombosis, and Vascular Biology, 29 (8). http://dx.doi.org/10.1161/ATVBAHA.109.189407