Peroxisome Proliferator–Activated Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-α Expression in Neonatal Rat Cardiac Myocytes

Abstract

Abstract —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-α (TNF-α) expression is elevated in the failing heart and that TNF-α has a negative inotropic effect on cardiac myocytes. Therefore, we examined the effects of PPARα and PPARγ activators on expression of TNF-α in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPARα and PPARγ mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPARα and PPARγ were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPARα and PPARγ activators increased the promoter activity. Cardiomyocytes were stimulated with lipopolysaccharide (LPS), and the levels of TNF-α in the medium were measured by ELISA. After exposure to LPS, the levels of TNF-α significantly increased. However, pretreatment of myocytes with PPARα or PPARγ activators decreased LPS-induced expression of TNF-α in the medium. Both PPARα and PPARγ activators also inhibited LPS-induced increase in TNF-α mRNA in myocytes. In addition, electrophoretic mobility shift assays demonstrated that PPAR activators reduced LPS-induced nuclear factor-κB activation. These results suggest that both PPARα and PPARγ activators inhibit cardiac expression of TNF-α in part by antagonizing nuclear factor-κB activity and that treatment with PPAR activators may lead to improvement in congestive heart failure.