Abstract
Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acute-Phase Proteins / metabolism
-
Animals
-
Anti-Inflammatory Agents / pharmacology
-
Aorta* / cytology
-
Aorta* / drug effects
-
Aorta* / enzymology
-
Aorta* / pathology
-
COS Cells
-
Coronary Disease / blood
-
Cyclooxygenase 2
-
Cyclooxygenase 2 Inhibitors
-
Cyclooxygenase Inhibitors / pharmacology
-
Fenofibrate / pharmacology
-
Gemfibrozil / pharmacology
-
Gene Expression Regulation, Enzymologic
-
Humans
-
Hyperlipidemias / blood
-
Hypolipidemic Agents / pharmacology
-
Inflammation / enzymology
-
Inflammation / metabolism
-
Interleukin-1 / metabolism
-
Interleukin-6 / biosynthesis
-
Isoenzymes / biosynthesis
-
Isoenzymes / genetics
-
Membrane Proteins
-
Muscle, Smooth, Vascular / drug effects
-
Muscle, Smooth, Vascular / pathology
-
Muscle, Smooth, Vascular / physiology*
-
NF-kappa B / metabolism
-
Prostaglandin-Endoperoxide Synthases / biosynthesis
-
Prostaglandin-Endoperoxide Synthases / genetics
-
Prostaglandins / biosynthesis
-
Pyrimidines / pharmacology
-
Receptors, Cytoplasmic and Nuclear / biosynthesis
-
Receptors, Cytoplasmic and Nuclear / chemistry
-
Receptors, Cytoplasmic and Nuclear / physiology*
-
Rosiglitazone
-
Thiazoles / pharmacology
-
Thiazolidinediones*
-
Transcription Factors / biosynthesis
-
Transcription Factors / chemistry
-
Transcription Factors / physiology*
-
Transcription, Genetic
Substances
-
Acute-Phase Proteins
-
Anti-Inflammatory Agents
-
Cyclooxygenase 2 Inhibitors
-
Cyclooxygenase Inhibitors
-
Hypolipidemic Agents
-
Interleukin-1
-
Interleukin-6
-
Isoenzymes
-
Membrane Proteins
-
NF-kappa B
-
Prostaglandins
-
Pyrimidines
-
Receptors, Cytoplasmic and Nuclear
-
Thiazoles
-
Thiazolidinediones
-
Transcription Factors
-
Rosiglitazone
-
pirinixic acid
-
Cyclooxygenase 2
-
PTGS2 protein, human
-
Prostaglandin-Endoperoxide Synthases
-
Gemfibrozil
-
Fenofibrate