Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.
Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.
复制标题
DOI：
10.1161/atvbaha.109.189407
复制
发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
McCaffrey TA
中科院分区：
文献类型：
--
作者：
Yang Z;Gagarin D;St Laurent G 3rd;Hammell N;Toma I;Hu CA;Iwasa A;McCaffrey TA
越来越多的证据表明，慢性炎症有助于动脉粥样硬化的形成，而急性炎症事件导致斑块破裂、血栓形成和心肌梗死。目前的研究探讨了炎症因子，如干扰素-γ（IFNγ），如何导致血管病变细胞对凋亡的敏感性增加。干扰素-γ（IFNγ）以Bcl-XL可逆的方式使人动脉粥样硬化病变纤维帽细胞对Fas诱导的凋亡敏感。微阵列分析鉴定了72个INFγ诱导的转录物，其与细胞凋亡可能相关。一半可以被排除，因为它们是由IRF-1过表达诱导的，而IRF-1对细胞凋亡不敏感。IFNγ处理强烈降低Mcl-1、磷酸化Bcl-2（ser 70）和磷酸化Bcl-XL（ser 62）蛋白水平。通过siRNA、过表达或抑制剂调节候选转录物，以评估对IFNγ诱导的Fas敏感性的影响。令人惊讶的是，PSMB 8（LMP 7）（一种“免疫蛋白酶体”组分）的siRNA敲低逆转了IFNγ诱导的对Fas连接的敏感性，并阻止了Fas/IFNγ诱导的Mcl-1降解，但不保护p-Bcl-2或p-Bcl-XL。IFNγ处理后，蛋白酶体抑制显著增加Mcl-1、p-Bcl-2和p-Bcl-XL水平。免疫蛋白酶体对抗原提呈至关重要，但它似乎是炎症因子和控制血管细胞凋亡之间的关键环节，因此可能是斑块破裂和心肌梗死的重要因素。
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. 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. While critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis, and thus may be an important factor in plaque rupture and myocardial infarction.