Article: article from journal or magazin.
PPARβ/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.
Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids
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.
AMP-Activated Protein Kinases/metabolism, Animals, Cell Line, Cells, Cultured, Dietary Fats/adverse effects, Dietary Fats/metabolism, Heart/drug effects, Humans, Inflammation/immunology, Lipids/pharmacology, Mice, Mice, Knockout, Myocardium/immunology, PPAR delta/agonists, PPAR delta/metabolism, PPAR-beta/agonists, PPAR-beta/metabolism, Signal Transduction/drug effects, Signal Transduction/immunology, Thiazoles/metabolism, Transcription Factor RelA/metabolism
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