PPARß/d activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.
Por:
Alvarez-Guardia D, Palomer FX, Coll T, Serrano L, Rodríguez-Calvo R, Davidson MM, Merlos M, El Kochairi I, Michalik L, Wahli W and Vazquez M
Publicada:
1 feb 2011
Resumen:
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-?B (NF-?B), 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-?B. Since PPARß/d is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPARß/d agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-a, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-?B 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. PPARß/d activation by GW501516 enhanced the physical interaction between PPARß/d and p65, which suggests that this mechanism may also interfere NF-?B transactivation capacity in the heart. GW501516-induced PPARß/d 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 PPARß/d has been postulated as a potential target in the treatment of obesity and the insulin resistance state.
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