Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced turner necrosis factor-α expression in neonatal rat cardiac myocytes

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Recently, PPAR activators have been shown to inhibit the production of proinflammatory cytokines in macrophages or vascular smooth muscle cells. It has been reported that tumor necrosis factor-alpha (TNF-alpha) expression is elevated in the failing heart and that TNF-alpha has a negative inotropic effect on cardiac myocytes. Therefore, we examined the effects of PPAR alpha and PPAR gamma activators on expression of TNF-alpha in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPAR alpha and PPAR gamma mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPAR alpha and PPAR gamma were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPAR alpha and PPAR gamma activators increased the promoter activity. Cardiomyocytes were stimulated with Lipopolysaccharide (LPS), and the levels of TNF-alpha in the medium were measured by ELISA. After exposure to LPS, the levels of TNF-alpha significantly increased. However, pretreatment of myocytes with PPAR alpha or PPAR gamma activators decreased LPS-induced expression of TNF-alpha in the medium. Both PPAR alpha and PPAR gamma activators also inhibited LPS-induced increase in TNF-alpha mRNA in myocytes. In addition, electrophoretic mobility shift assays demonstrated that PPAR activators reduced LPS-induced nuclear factor-kappa B activation. These results suggest that both PPAR alpha and PPAR gamma activators inhibit cardiac expression of TNF-alpha in part by antagonizing nuclear factor-kappa B activity and that treatment with PPAR activators may lead to improvement in congestive heart failure.