[Effects of PPAR-gamma agonist rosiglitazone on MMP-9 and TIMP-1 expression of monocyte-derived macrophages isolated from patients with acute coronary syndrome].
OBJECTIVE
Coronary arterial plaque rupture and secondary thrombosis are the major pathogenesis of acute coronary syndrome (ACS). Metalloprotease (MMPs) secreted by monocyte/macrophage was the main predisposing factor of the plaque rupture and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in a variety of inflammatory cytokine gene transcriptional regulations. We explored the possible role of PPAR-gamma in the regulation of MMP-9 and TIMP-1 expressed by peripheral monocyte-derived macrophages (MDMs) from patients with ACS.


METHODS
Peripheral blood mononuclear cells were isolated from 48 patients with ACS and 28 healthy controls and stimulated by macrophage colony-stimulating factor (0.1 microg/ml for 24 hours) to form MDMs. MDMs were then incubated under various concentrations of rosiglitazone (0, 1, 10, 20 micromol/L) for 48 hours. The concentrations of MMP-9 and TIMP-1 in the supernatant were measured by enzyme linked immunosorbent assay, and the mRNA expression of PPAR-gamma, MMP-9 by RT-PCR and nuclear factor-kappaB P65 (NF-kappaB P65) expression by immunohistochemistry.


RESULTS
PPAR-gamma mRNA expression was significantly lower while NF-kappaB P65 and MMP-9 expression as well as MMP-9 and TIMP-1 concentrations in supernatant were significantly higher in ACS group than those in control group (all P < 0.05). After rosiglitazone intervention, PPAR-gamma mRNA expression was significantly upregulated in both ACS and control groups in a dose-dependent manner. Both the MMP-9 concentration in the supernatant and MMP-9 mRNA expression were reduced post intervention with rosiglitazone in both groups. The TIMP-1 mRNA expression and concentration in supernatant were not affected by rosiglitazone in both groups. Rosiglitazone induced significant downregulation of NF-kappaB P65 expression in both groups.


CONCLUSIONS
Rosiglitazone intervention may downregulate MMP-9 expression by upregulating PPAR-gamma expression, and by downregulating NF-kappaB expression in MDMs isolated from patients with ACS.
Luo
Yu-mei
YM
Department of Cardiology, Longgang People's Hospital, Shenzhen 518172, China. yumeiluo2000@yahoo.com.cn
Wan
Xin-hong
XH
Jiang
De-qian
DQ
Kuang
Wen-yong
WY
Guo
Hong-bo
HB
Chen
Zhao-xia
ZX
Wang
He-jin
HJ
Xie
Li-hua
LH
Duan
Wen
W
D054058:Acute Coronary Syndrome / Q000097:blood*; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D047495:PPAR gamma; C498143:RELA protein, human; D045162:Thiazolidinediones; D019715:Tissue Inhibitor of Metalloproteinase-1; D051996:Transcription Factor RelA; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D020780:Matrix Metalloproteinase 9