Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.
Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.
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DOI：
10.1126/scitranslmed.aal3765
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发表时间：
2017-12-13
影响因子：
17.1
通讯作者：
Tager AM
中科院分区：
文献类型：
--
作者：
Lagares D;Santos A;Grasberger PE;Liu F;Probst CK;Rahimi RA;Sakai N;Kuehl T;Ryan J;Bhola P;Montero J;Kapoor M;Baron M;Varelas X;Tschumperlin DJ;Letai A;Tager AM
持续性肌成纤维细胞活化将病理性纤维化与生理性伤口愈合区分开来，表明选择性诱导肌成纤维细胞凋亡的疗法可以防止疾病进展并可能逆转疾病（如硬皮病，一种以多器官纤维化为特征的异质性自身免疫性疾病）中已建立的纤维化。我们证明，由基质硬度驱动的成纤维细胞到肌成纤维细胞的分化增加了这些活化细胞的线粒体启动（接近凋亡阈值）。激活的肌成纤维细胞中的线粒体，而不是静止的成纤维细胞，被死亡信号如促凋亡BH 3-only蛋白BIM引发，这产生了对抗凋亡蛋白BCL-XL的紧张性表达的需要，以隔离BIM并确保肌成纤维细胞存活。肌成纤维细胞变得对抑制BCL-XL的“BH 3模拟物”药物如ABT-263诱导的细胞凋亡特别敏感。ABT-263取代BCL-XL与BIM的结合，使BIM能够激活僵硬引发的肌成纤维细胞的凋亡。用ABT-263（navitoclax）治疗性阻断BCL-XL通过诱导肌成纤维细胞凋亡有效地治疗硬皮病皮肤纤维化小鼠模型中建立的纤维化。使用BH 3谱分析来评估硬皮病患者皮肤成纤维细胞的线粒体启动，我们证明BH 3模拟药物诱导的细胞凋亡程度与其线粒体启动程度相关，这表明BH 3谱分析可以预测成纤维细胞对BH 3的细胞凋亡反应硬皮病患者的模拟药物。总之，我们的研究结果阐明了BH 3模拟药物靶向肌成纤维细胞抗凋亡蛋白在硬皮病和其他纤维化疾病中的潜在疗效。
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-XL to sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by “BH3 mimetic” drugs inhibiting BCL-XL such as ABT-263. ABT-263 displaces BCL-XL binding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-XL with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.
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影响因子：
82.9
作者：
通讯作者：
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DOI：
10.1083/jcb.201501025
发表时间：
2015-08-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim NG;Gumbiner BM
通讯作者：
Gumbiner BM
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
DOI：
10.1073/pnas.1201840109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Kisseleva, Tatiana;Cong, Min;Brenner, David A.
通讯作者：
Brenner, David A.
在硬皮病小鼠模型中通过基因缺失或溶血磷脂酸受体 1 的药理学拮抗作用改善真皮纤维化。
影响因子：
--
作者：
Castelino, Flavia V.;Seiders, Jon;Bain, Gretchen;Brooks, Sarah F.;King, Christopher D.;Swaney, James S.;Lorrain, Daniel S.;Chun, Jerold;Luster, Andrew D.;Tager, Andrew M.
通讯作者：
Tager, Andrew M.