Macrophages in human atheroma contain PPARγ -: Differentiation-dependent peroxisomal proliferator-activated receptorγ (PPARγ) expression and reduction of MMP-9 activity through PPARγ 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 (PPAR gamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-(Delta 12,14)-prostaglandin J(2) and the antidiabetic agent troglitazone. The role of PPAR gamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPAR gamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPAR gamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPAR gamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPAR gamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPAR gamma with troglitazone or 15-deoxy-(Delta 12,) (14)-prostaglandin J(2) 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, PPAR gamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPAR gamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.