PPARβ/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.
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.
Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
David
D
Alvarez-Guardia
Xavier
X
Palomer
Teresa
T
Coll
Lucía
L
Serrano
Ricardo
R
Rodríguez-Calvo
Mercy M
MM
Davidson
Manuel
M
Merlos
Ilhem
I
El Kochairi
Liliane
L
Michalik
Walter
W
Wahli
Manuel
M
Vázquez-Carrera
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008055:Lipids / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013844:Thiazoles / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D004041:Dietary Fats; C425931:GW 501516; D008055:Lipids; D047494:PPAR delta; D048068:PPAR-beta; C498144:Rela protein, mouse; D013844:Thiazoles; D051996:Transcription Factor RelA; D055372:AMP-Activated Protein Kinases