Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy
Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy
复制标题
含有 1 的靶向跨膜 BAX 抑制剂基序可减轻病理性心脏肥大
DOI：
10.1161/circulationaha.117.031659
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发表时间：
2018-04-03
期刊：
影响因子：
37.8
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
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作者：
Deng, Ke-Qiong;Zhao, Guang-Nian;Li, Hongliang
背景：心脏肥大及其导致的心力衰竭是世界范围内最常见的死亡原因之一。异常的蛋白质降解，特别是大细胞器和膜蛋白的溶酶体降解受损，参与心肌肥大的进展。然而，其潜在的机制尚未完全阐明。方法：我们研究心脏跨膜BAX抑制剂基序包含1（TMBIM 1）的mRNA和蛋白表达水平的样品从心力衰竭患者和小鼠与主动脉束带（AB）诱导的心脏肥大。我们产生了心脏特异性Tmbim 1敲除小鼠和心脏特异性Tmbim 1过表达转基因小鼠，然后用AB手术对其进行攻击。我们使用微阵列、共聚焦图像和免疫共沉淀分析来鉴定心肌肥大中TMBIM 1的下游靶点。建立Tmbim 1/Tlr 4双基因敲除小鼠模型，研究Tmbim 1对心肌肥厚的作用是否依赖于Toll样受体4（TLR 4）。最后，在猴AB模型中进行慢病毒介导的TMBIM 1过表达，以评估TMBIM 1的治疗潜力。结果：TMBIM 1在人和小鼠心脏样品中的表达在肥大刺激下均显著下调。沉默心脏Tmbim 1可加重AB诱导的心肌肥厚。这种作用被Tmbim 1过表达减弱。转录组分析显示，TLR 4信号通路被Tmbim 1的操纵显着破坏。在双敲除小鼠中，TMBIM 1对心脏肥大的作用显示依赖于TLR 4。荧光染色显示TMBIM 1促进溶酶体介导的活化TLR 4的降解。免疫共沉淀实验证实TMBIM 1通过PTAP基序直接与肿瘤易感基因101相互作用，并加速多泡体的形成，从而将TLR 4递送至溶酶体。最后，慢病毒介导的TMBIM 1过表达逆转AB诱导的猴心肌肥厚。结论：TMBIM 1通过促进激活的TLR 4的溶酶体降解来防止病理性心肌肥厚。我们的研究结果揭示了TMBIM 1作为多泡体调节剂在病理性心脏肥大进展中的核心作用，以及囊泡运输在心脏肥大期间信号调节中的作用。此外，靶向TMBIM 1可能是治疗心脏肥大和心力衰竭的新的治疗策略。
BACKGROUND: Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide. Abnormal protein degradation, especially the impaired lysosomal degradation of large organelles and membrane proteins, is involved in the progression of cardiac hypertrophy. However, the underlying mechanisms have not been fully elucidated.METHODS: We investigated cardiac transmembrane BAX inhibitor motif containing 1 (TMBIM1) mRNA and protein expression levels in samples from patients with heart failure and mice with aortic banding (AB)-induced cardiac hypertrophy. We generated cardiac-specific Tmbim1 knockout mice and cardiac-specific Tmbim1-overexpressing transgenic mice and then challenged them with AB surgery. We used microarray, confocal image, and coimmunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy. Tmbim1/Tlr4 double-knockout mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were Toll-like receptor 4 (TLR4) dependent. Finally, lentivirus-mediated TMBIM1 overexpression in a monkey AB model was performed to evaluate the therapeutic potential of TMBIM1.RESULTS: TMBIM1 expression was significantly downregulated on hypertrophic stimuli in both human and mice heart samples. Silencing cardiac Tmbim1 aggravated AB-induced cardiac hypertrophy. This effect was blunted by Tmbim1 overexpression. Transcriptome profiling revealed that the TLR4 signaling pathway was disrupted dramatically by manipulation of Tmbim1. The effects of TMBIM1 on cardiac hypertrophy were shown to be dependent on TLR4 in double-knockout mice. Fluorescent staining indicated that TMBIM1 promoted the lysosome-mediated degradation of activated TLR4. Coimmunoprecipitation assays confirmed that TMBIM1 directly interacted with tumor susceptibility gene 101 via a PTAP motif and accelerated the formation of multivesicular bodies that delivered TLR4 to the lysosomes. Finally, lentivirus-mediated TMBIM1 overexpression reversed AB-induced cardiac hypertrophy in monkeys.CONCLUSIONS: TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4. Our findings reveal the central role of TMBIM1 as a multivesicular body regulator in the progression of pathological cardiac hypertrophy, as well as the role of vesicle trafficking in signaling regulation during cardiac hypertrophy. Moreover, targeting TMBIM1 could be a novel therapeutic strategy for treating cardiac hypertrophy and heart failure.