PPARδ modulates lipopolysaccharide-induced TNFα inflammation signaling in cultured cardiomyocytes

Peroxisome proliferator activated receptors (PPARs: PPARα, γ and δ) regulate fatty acid metabolism, glucose homeostasis, cell proliferation, differentiation and inflammation. Tumor necrosis factor α (TNFα) is one of the important pathological factors in inflammatory responses during the pathological progression of myocardial ischemic/reperfusion and hypertrophy. Accumulating evidence shows that synthetic ligands of PPARα and PPARγ suppress myocardial inflammatory responses, such as the production of TNFα, thus exerting beneficial effects in animals who had undergone ischemia/reperfusion injury or cardiac hypertrophy. However, it remains obscured if PPARδ and its ligands exert any effect on the production of TNFα, thus influencing cardiac inflammatory responses. In this study, we investigated the effects of PPARδ and its synthetic ligand GW0742 on TNFα production in cultured cardiomyocytes. Our studies indicate that a PPARδ-selective ligand inhibited lipopolysaccharide (LPS)-induced TNFα production from cardiomyocytes. Adenoviral-mediated overexpression of PPARδ substantially inhibited TNFα expression in cultured cardiomyocytes compared to controls, whereas overexpression of a PPARδ mutant with ablated ligand binding domain did not show similar effect. Conversely, absence of PPARδ in cardiomyocytes further exaggerated LPS-induced TNFα production. Moreover, activation of PPARδ abrogated LPS-induced degradation of IκBs, thus suppressing LPS-induced nuclear factor κB (NF-κB) activities. Therefore, PPARδ is an important determinant of TNFα expression via the NF-κB signaling pathway, thus serving as therapeutic targets to attenuate inflammation that are involved in cardiac pathological progression.