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

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-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 PPARalpha and PPARgamma activators on expression of TNF-alpha in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPARalpha and PPARgamma mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPARalpha and PPARgamma were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPARalpha and PPARgamma 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 PPARalpha or PPARgamma activators decreased LPS-induced expression of TNF-alpha in the medium. Both PPARalpha and PPARgamma 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-kappaB activation. These results suggest that both PPARalpha and PPARgamma activators inhibit cardiac expression of TNF-alpha in part by antagonizing nuclear factor-kappaB activity and that treatment with PPAR activators may lead to improvement in congestive heart failure.

Inflammatory Pathways Are Activated during Cardiomyocyte Hypertrophy and Attenuated by Peroxisome Proliferator-activated Receptors PPARα and PPARδ

“…Stimulation of NCM with TNF-␣ did not give rise to a significant increase in NCM size. In line with previous studies (10,26), infection with AdPPAR␣ or AdPPAR␦ blunted the TNF-␣ induced expression of inflammatory markers like COX-2 (data not shown).…”

The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chainn-3 PUFA

“…PUFA are potent PPAR activators leading to the increased expression of genes responsible for fatty acid oxidation such as acyl-CoA oxidase, fatty acyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase (87,88) . Activators of PPAR have been shown to inhibit the activation of inflammatory genes including TNFa, IL-1b, IL-6, IL-8, cyclooxygenase-2, vascular cell adhesion molecule-1, inducible NO synthase, matrix metalloproteinases and acute-phase proteins (89)(90)(91)(92)(93)(94)(95)(96) . Two mechanisms for the anti-inflammatory actions of PPAR have been proposed (97,98) .…”

Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil

“…It has been found to decrease serum triglycerides and very low density lipoprotein-cholesterol (VLDL) and to increase high density lipoprotein-cholesterol (HDL) (Kersten et al, 2000) by activating the peroxisome proliferator activated receptors (PPARs), acting mainly on the PPAR isoform (Loomba and Arora, 2009;Fruchart and Duriez, 2006). Additional effects have been noted including their anti-inflammation 75 effects (Takano et al, 2000;Delerive et al, 2001;Marx, 2002), inflammatory process plays an important role in the pathogenesis of coronary heart disease (Zhao et al, 2003). Gemfibrozil has been previously shown to reduce some indexes of thrombin generation, without affecting or even raising plasma fibrinogen levels (Wilkes et al, 1992;Broijersen et al, 1996;Kockx et al, 1997).…”