In vitro modulation of peroxisome proliferator-activated receptor-gamma and its genes by C-reactive protein. Role of atorvastatin.
OBJECTIVE
C-reactive protein (CRP) serves not only as a biomarker for the risk of cardiovascular disease and underlying inflammation but also functions as an active mediator of atherosclerosis by promoting activation of endothelial cells and monocytes. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) transcription factor has been recognized to regulate the expression of many genes involved in inflammation, lipid metabolism and vascular remodeling. Therefore, in the present study we tried to explore the role of CRP as a possible mediator of atherosclerosis by determining its effect on PPAR-gamma and its effector genes, i.e., liver X receptor-alpha (LXR-alpha) and matrix metalloproteinase-9 (MMP-9) in THP-1 cells.


METHODS
Semi-quantitative RT-PCR was used to determine mRNA expression.


RESULTS
CRP upregulates the expression of PPAR-gamma and LXR-alpha at lower doses (5-25 microg/mL), which were further declined at higher doses (50-100 microg/mL). However, a dose-dependent increase was observed for MMP-9 expression. Atorvastatin (10-20 microM) was able to significantly accelerate the CRP-induced expression of PPAR-gamma and LXR-alpha and attenuate MMP-9 expression.


CONCLUSIONS
For the first time we demonstrate that CRP modulates PPAR-gamma and its effector genes and reinforces the mechanistic link of CRP as a possible mediator in atherosclerosis and also advocate atorvastatin as a therapeutic modality.
Mahajan
Nitin
N
Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
Dhawan
Veena
V
D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000069059:Atorvastatin; D001483:Base Sequence; D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000071518:Liver X Receptors; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D011758:Pyrroles; D012333:RNA, Messenger; D002097:C-Reactive Protein; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9