The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells
The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells
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DOI：
10.1093/cvr/cvq080
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发表时间：
2010-08-01
影响因子：
10.8
通讯作者：
Vazquez-Carrera, Manuel
中科院分区：
文献类型：
--
作者：
Alvarez-Guardia, David;Palomer, Xavier;Vazquez-Carrera, Manuel
核因子-κ B（NF-κ B）是一种由多种刺激诱导的转录因子，包括高脂血症和促炎细胞因子。它与心脏肥大和心力衰竭有关。以前有报道称，NF-κ B介导的增殖物激活受体-γ共激活因子-1 α（PGC-1 α）的抑制可能解释了促炎刺激诱导的心脏病理过程中葡萄糖代谢的变化，但具体机制仍有待阐明。我们探讨了暴露于肿瘤坏死因子-α的具体机制，肿瘤坏死因子-α（TNF-α）导致心肌细胞中PGC-1 α下调，因此导致代谢失调，这是心脏功能障碍和衰竭的基础。我们首次报道了NF-κ B的p65亚单位在人心脏细胞和小鼠心脏中组成性结合于PGC-1 α，并且通过TNF-α暴露的NF-κ B活化增加了这种结合。过表达和基因沉默分析表明，限制这种关联程度的主要因素是p65，因为只有这种蛋白质的调节才能改变物理相互作用。我们的数据表明，NF-κ B激活后p65和PGC-1 α之间的物理相互作用增加是导致PGC-1 α表达减少和随后葡萄糖氧化失调的原因。从而导致丙酮酸脱氢酶激酶4（PDK 4）表达的减少和随后在促炎状态期间观察到的葡萄糖氧化的增加。
Nuclear factor-kappa B (NF-kappa B) is a transcription factor induced by a wide range of stimuli, including hyperglycaemia and pro-inflammatory cytokines. It is associated with cardiac hypertrophy and heart failure. It was previously reported that the NF-kappa B-mediated inhibition of proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) might explain the shift in glucose metabolism during cardiac pathological processes induced by pro-inflammatory stimuli, although the specific mechanisms remain to be elucidated. We addressed the specific mechanisms by which exposure to tumour necrosis factor-alpha (TNF-alpha) results in PGC-1 alpha down-regulation in cardiac cells and, as a consequence, in the metabolic dysregulation that underlies heart dysfunction and failure.By using coimmunoprecipitation studies, we report for the first time that the p65 subunit of NF-kappa B is constitutively bound to PGC-1 alpha in human cardiac cells and also in mouse heart, and that NF-kappa B activation by TNF-alpha exposure increases this binding. Overexpression and gene silencing analyses demonstrated that the main factor limiting the degree of this association is p65, because only the modulation of this protein modified the physical interaction. Our data show that the increased physical interaction between p65 and PGC-1 alpha after NF-kappa B activation is responsible for the reduction in PGC-1 alpha expression and subsequent dysregulation of glucose oxidation.On the basis of these data, we propose that p65 directly represses PGC-1 alpha activity in cardiac cells, thereby leading to a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and the subsequent increase in glucose oxidation observed during the proinflammatory state.