Rosiglitazone suppresses lipopolysaccharide-induced matrix metalloproteinase-2 activity in rat aortic endothelial cells via Ras-MEK1/2 signaling.
OBJECTIVE
Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of chronic inflammatory disease, such as atherosclerosis. Among MMPs, MMP-2 is regarded as a major proteinase in atherosclerotic plaque lesions. Peroxisome proliferator activated receptor-gamma (PPARγ) ameliorates oxidative stress and the inflammatory response. The aim of the present study was to evaluate the effect of Rosiglitazone on lipopolysaccharide (LPS)-induced MMP-2 activation as well as its possible mechanism.


METHODS
Primary culture of rat aortic endothelial cells (RAEC) was derived from male Sprague-Dawley rat. MMP-2 activity was assayed by gelatin zymography. Protein expressions were determined by Western Blotting. DNA binding activity of NF-κB was studied with electrophoretic mobility shift assay.


RESULTS
LPS-induced MMP-2 activity was inhibited by Rosiglitazone (PPARγ agonist) in the rat aortic endothelial cells (RAEC). LPS-induced MMP-2 activation was diminished due to exposure to NF-κB Activation Inhibitor II (JSH-23) or Ras inhibitor, farnesylthiosalicylic acid (FTS). Further study shows that LPS-induced activation of Phospho-Ras homologue gene family, member A (Rho A) and Phospho-mitogen-activated protein kinase kinase 1/2 (MEK1/2) were significantly inhibited by Rosiglitazone. The activation of NF-κB p65 in the nuclear extract of cells was also significantly suppressed by Rosiglitazone, moreover, the expression of NF-κB p65 was partly activated by GW9662 (PPARγ antagonist). NF-κB DNA binding activity was also demolished by Rosiglitazone.


CONCLUSIONS
Our data shows that PPARγ agonist, Rosiglitazone suppresses LPS-activated MMP-2 secretion via Ras-MEK1/2 signaling pathways and NF-κB activation. PPARγ agonist and Ras-MEK1/2 pathway may be another potential therapeutic target for the disease induced by chronic inflammation.
Department of Cardiology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China. whw780@gmail.com
Xianghong
X
Wu
Lang
L
Li
D000818:Animals; D001011:Aorta / Q000166:cytology*; D042783:Endothelial Cells / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D018631:ras Proteins / Q000502:physiology*
D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048369:MAP Kinase Kinase 1; D020778:Matrix Metalloproteinase 2; D018631:ras Proteins