TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model (Publication with Expression of Concern. See vol. 14, 2019)
TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model (Publication with Expression of Concern. See vol. 14, 2019)
复制标题
DOI：
10.1093/cvr/cvn327
复制
发表时间：
2009-03-01
影响因子：
10.8
通讯作者：
Vazquez-Carrera, Manuel
中科院分区：
文献类型：
--
作者：
Palomer, Xavier;Alvarez-Guardia, David;Vazquez-Carrera, Manuel
心脏中由细胞因子持续增加所驱动的炎症反应与一些病理过程有关，包括心脏肥大和心力衰竭。新出现的数据表明，心肌病和心肌代谢失调之间存在联系。为了进一步阐明促炎因子与心脏代谢紊乱之间的关系，用肿瘤坏死因子-α(TNF-α)处理人心脏源性细胞系AC16。肿瘤坏死因子-α可抑制脂质和葡萄糖氧化代谢上游调节因子--过氧化体增殖物激活受体共激活因子1α(PGC-1α)的表达。对心脏特异的转基因小鼠(Mus Musculus)进行的研究也显示，与对照组小鼠相比，心脏中PGC-1α的表达减少。在体外，肿瘤坏死因子α降低PGC-1α表达的机制似乎主要是通过p38丝裂原活化蛋白激酶和核因子-kappa B途径来调节的。PGC-1α下调导致葡萄糖氧化率增加，这涉及丙酮酸脱氢酶激酶4的表达减少，并依赖于过氧化体增殖物激活受体β/增量和雌激素相关受体α转录因子的DNA结合活性。这些结果表明，PGC-1α下调可能是炎症背景代谢性疾病心脏功能障碍和心力衰竭的潜在贡献者。
Inflammatory responses in the heart that are driven by sustained increases in cytokines have been associated with several pathological processes, including cardiac hypertrophy and heart failure. Emerging data suggest a link between cardiomyopathy and myocardial metabolism dysregulation. To further elucidate the relationship between a pro-inflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumour necrosis factor-alpha (TNF-alpha).Exposure of AC16 cells to TNF-alpha inhibited the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1 alpha), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-alpha, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1 alpha expression in the heart compared with that of control mice. The mechanism by which TNF-alpha reduced PGC-1 alpha expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-kappa B pathways. PGC-1 alpha downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 expression and depended on the DNA-binding activity of both peroxisome proliferator-activated receptor beta/delta and estrogen-related receptor alpha transcription factors.These results point to PGC-1 alpha downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.