Alvarez-Guardia David, Palomer Xavier, Coll Teresa, Serrano Lucía, Rodríguez-Calvo Ricardo, Davidson Mercy M, Merlos Manuel, El Kochairi Ilhem, Michalik Liliane, Wahli Walter, Vázquez-Carrera Manuel
Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
Biochim Biophys Acta. 2011 Feb;1811(2):59-67. doi: 10.1016/j.bbalip.2010.11.002. Epub 2010 Nov 9.
Owing to its high fat content, the classical Western diet has a range of adverse effects on the heart, including enhanced inflammation, hypertrophy, and contractile dysfunction. Proinflammatory factors secreted by cardiac cells, which are under the transcriptional control of nuclear factor-κB (NF-κB), may contribute to heart failure and dilated cardiomyopathy. The underlying mechanisms are complex, since they are linked to systemic metabolic abnormalities and changes in cardiomyocyte phenotype. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolism and are capable of limiting myocardial inflammation and hypertrophy via inhibition of NF-κB. Since PPARβ/δ is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPARβ/δ agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-κB in the heart of mice. GW501516 abrogated this enhanced proinflammatory profile. Similar results were obtained when human cardiac AC16 cells exposed to palmitate were coincubated with GW501516. PPARβ/δ activation by GW501516 enhanced the physical interaction between PPARβ/δ and p65, which suggests that this mechanism may also interfere NF-κB transactivation capacity in the heart. GW501516-induced PPARβ/δ activation can attenuate the inflammatory response induced in human cardiac AC16 cells exposed to the saturated fatty acid palmitate and in mice fed a high-fat diet. This is relevant, especially taking into account that PPARβ/δ has been postulated as a potential target in the treatment of obesity and the insulin resistance state.
由于其高脂肪含量，传统西方饮食对心脏有一系列不良影响，包括炎症增强、肥大和收缩功能障碍。心脏细胞分泌的促炎因子受核因子-κB（NF-κB）的转录控制，可能导致心力衰竭和扩张型心肌病。潜在机制很复杂，因为它们与全身代谢异常和心肌细胞表型变化有关。过氧化物酶体增殖物激活受体（PPARs）是调节代谢的转录因子，能够通过抑制NF-κB来限制心肌炎症和肥大。由于PPARβ/δ是心脏中最普遍的PPAR亚型，我们分析了PPARβ/δ激动剂GW501516对炎症参数的影响。高脂饮食诱导肿瘤坏死因子-α、单核细胞趋化蛋白-1和白细胞介素-6的表达，并增强小鼠心脏中NF-κB的活性。GW501516消除了这种增强的促炎状态。当暴露于棕榈酸的人心脏AC16细胞与GW501516共同孵育时，也得到了类似的结果。GW501516激活PPARβ/δ增强了PPARβ/δ与p65之间的物理相互作用，这表明该机制也可能干扰心脏中NF-κB的反式激活能力。GW501516诱导的PPARβ/δ激活可减弱在暴露于饱和脂肪酸棕榈酸的人心脏AC16细胞和高脂饮食喂养的小鼠中诱导的炎症反应。这一点很重要，特别是考虑到PPARβ/δ已被假定为肥胖和胰岛素抵抗状态治疗的潜在靶点。
