Up regulated Tmbim1 activation promotes high fat diet (HFD)-induced cardiomyopathy by enhancement of inflammation and oxidative stress
Up regulated Tmbim1 activation promotes high fat diet (HFD)-induced cardiomyopathy by enhancement of inflammation and oxidative stress
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DOI：
10.1016/j.bbrc.2018.08.059
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发表时间：
2018-10-12
影响因子：
3.1
通讯作者：
Wang, Haijun
中科院分区：
文献类型：
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作者：
Gong, Fen;Gu, Junfei;Wang, Haijun
代谢应激引起的心肌病发病率显著上升；然而，其分子机制尚不清楚。本研究表明，含1的跨膜BAX抑制剂基序（Tmbim1）在高脂饮食（HFD）小鼠心脏中下调。我们提供的证据表明，Tmbim1敲除（KO）加速了hfd诱导的小鼠代谢紊乱，这得到了空腹血糖和胰岛素水平显著升高的支持。hfd诱导的心功能障碍由于Trribim1的缺失，以及血清中乳酸脱氢（LDH）和肌酸激酶（CK）水平升高而大大加剧。此外，Tmbim1的缺失显著增加了HFD小鼠心脏的脂质积累。此外，敲除Tmbim1可增强心肌炎症，其表现为促炎细胞因子(白细胞介素1 β （IL-1 β)、IL-6和肿瘤坏死因子α (tnf - α)）的表达增加，核因子κ B （nf - κ B）信号通路的激活。Tmbiml缺乏增强了hfd喂养小鼠心脏的氧化损伤，并伴有核因子-红细胞2相关因子2 （Nrf-2）通路的显著减少。在棕榈酸盐（PA）处理的原代心肌细胞中，Tmbim1消融显著增强了细胞炎症和氧化应激，这些炎症和氧化应激通过抑制ROS生成和NF-kappa B激活而被消除。综上所述，这些发现表明Tmbim1可能是代谢应激性心肌病的关键抑制因子，可能是治疗代谢综合征引发的心肌损伤和心力衰竭的一个有希望的靶点。(C) 2018年Elsevier Inc.出版
The prevalence of cardiomyopathy due to metabolic stress has up-regulated dramatically; nevertheless, its molecular mechanisms remain unclear. Here we suggested that transmembrane BAX inhibitor motif containing 1 (Tmbim1) is down-regulated in the hearts of mice fed with high fat diet (HFD). We provided evidence that Tmbim1 knockout (KO) accelerated HFD-induced metabolic disorders in mice, as supported by the remarkable increase of fasting serum glucose and insulin levels. HFD-induced cardiac dysfunctions were greatly intensified by the loss of Trribim1, along with higher levels of lactate dehydrogenate (LDH) and creatine kinase (CK) in serum. In addition, Tmbim1 deletion significantly enhanced lipid accumulation in heart of mice administrated with HFD. Furthermore, Tmbim1 knockout reinforced myocardial inflammation, evidenced by increasing the expression of pro-inflammatory cytokines (interleukin 1 beta (IL-1 beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha)), and the activation of nuclear factor-kappa B (NF-kappa B) signaling pathway. Tmbiml deficiency strengthened oxidative damage in hearts of HFD-fed mice, accompanied with a significant reduction of nuclear factor-erythroid 2 related factor 2 (Nrf-2) pathway. In palmitate (PA)-treated primary cardiomyocytes, Tmbim1 ablation markedly enhanced cell inflammation and oxidative stress, which were abolished by the suppression of ROS generation and NF-kappa B activation. Taken together, these findings suggested that Tmbim1 might be a key suppressor of metabolic stress-induced cardiomyopathy, which could be a promising target for the treatment of metabolic syndrome-triggered myocardial damage and heart failure. (C) 2018 Published by Elsevier Inc.