Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro.
Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-prostaglandin J2 in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
N
N
Marx
G
G
Sukhova
C
C
Murphy
P
P
Libby
J
J
Plutzky
D001161:Arteriosclerosis / Q000201:enzymology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D017364:Collagenases / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone
D002839:Chromans; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D000077288:Troglitazone; D013755:Tetradecanoylphorbol Acetate; D015230:Prostaglandin D2