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

Peroxisome proliferator-activated receptors (PPARs) are transcription facto rs 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 tumo r necrosis factor-alpha (TNF-alpha) expression is elevated in the failing h eart and that TNF-alpha has a negative inotropic effect on cardiac myocytes . Therefore, we examined the effects of PPAR alpha and PPAR gamma activator s on expression of TNF-alpha in neonatal rat cardiac myocytes. Northern blo t 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 we re transfected with PPAR responsive element (PPRE)-luciferase reporter plas mid, both PPAR alpha and PPAR gamma activators increased the promoter activ ity. 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, pretreatmen t of myocytes with PPAR alpha or PPAR gamma activators decreased LPS-induce d expression of TNF-alpha in the medium. Both PPAR alpha and PPAR gamma act ivators also inhibited LPS-induced increase in TNF-alpha mRNA in myocytes. In addition, electrophoretic mobility shift assays demonstrated that PPAR a ctivators reduced LPS-induced nuclear factor-kappa B activation. These resu lts suggest that both PPAR alpha and PPAR gamma activators inhibit cardiac expression of TNF-alpha in part by antagonizing nuclear factor-kappa B acti vity and that treatment with PPAR activators may lead to improvement in con gestive heart failure.