Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells
Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells
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DOI：
10.1074/jbc.m110.210245
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Hu, Chien-An A.
中科院分区：
文献类型：
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作者：
Zhaorigetu, Siqin;Yang, Zhaoqing;Hu, Chien-An A.
炎症细胞因子调控的细胞凋亡和自噬在动脉粥样硬化斑块破裂和血栓形成中起关键作用。然而，血管细胞凋亡和自噬之间的分子相互作用尚未被研究。我们之前的研究表明，人载脂蛋白L6 （ApoL6）是Bcl-2家族中促凋亡的bh3成员，是干扰素γ (INF γ)的下游靶点之一，干扰素γ可使动脉粥样硬化病变源性细胞（ldc）对fas诱导的凋亡敏感。为了研究ApoL6是否在动脉粥样硬化细胞凋亡和自噬中起因果作用，本研究证明IFN γ治疗本身强烈诱导ApoL6，并且在动脉粥样硬化病变活化的平滑肌细胞中，ApoL6高表达并与活化的caspase 3部分共定位。此外，过表达ApoL6可促进活性氧（ROS）的生成、caspase的激活和随后的细胞凋亡，这一过程可被泛caspase抑制剂和ROS清除剂阻断。siApoL6敲低ApoL6表达可抑制INF -和fas介导的细胞凋亡。此外，ApoL6结合最不发达国家中最丰富的抗死亡蛋白之一Bcl-X-L。有趣的是，在最不发达国家中，强迫ApoL6表达会诱导Beclin 1的降解，p62的积累，以及随后LC3-II形成和易位的衰减，从而导致自噬，而siApoL6处理会恢复表型。综上所述，我们的研究结果表明，ApoL6调节SMCs的凋亡和自噬。IFN γ启动的apol6诱导的血管细胞凋亡可能是导致斑块不稳定的重要因素，也是治疗动脉粥样硬化和心血管疾病的潜在治疗靶点。
Inflammatory cytokine-regulated apoptosis and autophagy play pivotal roles in plaque rupture and thrombosis of atherosclerotic lesions. However, the molecular interplay between apoptosis and autophagy in vascular cells has not been investigated. Our prior study showed that human apolipoprotein L6 (ApoL6), a pro-apoptotic BH3-only member of the Bcl-2 family, was one of the downstream targets of interferon-gamma (INF gamma), which sensitizes atherosclerotic lesion-derived cells (LDCs) to Fas-induced apoptosis. To investigate whether ApoL6 plays a causal role in atherosclerotic apoptosis and autophagy, in this study, we demonstrate that IFN gamma treatment itself strongly induces ApoL6, and ApoL6 is highly expressed and partially co-localized with activated caspase 3 in activated smooth muscle cells in atherosclerotic lesions. In addition, overexpression of ApoL6 promotes reactive oxygen species (ROS) generation, caspase activation, and subsequent apoptosis, which can be blocked by pan caspase inhibitor and ROS scavenger. Knockdown of ApoL6 expression by siApoL6 suppresses INF gamma- and Fas-mediated apoptosis. Further, ApoL6 binds Bcl-X-L, one of the most abundant anti-death proteins in LDCs. Interestingly, forced ApoL6 expression in LDCs induces degradation of Beclin 1, accumulation of p62, and subsequent attenuation of LC3-II formation and translocation and thus autophagy, whereas siApoL6 treatment reverts the phenotype. Taken together, our results suggest that ApoL6 regulates both apoptosis and autophagy in SMCs. IFN gamma-initiated, ApoL6-induced apoptosis in vascular cells may be an important factor causing plaque instability and a potential therapeutic target for treating atherosclerosis and cardiovascular disease.