MACROPHAGES IN HUMAN ATHEROMA CONTAIN PPAR-GAMMA - DIFFERENTIATION-DEPENDENT PEROXISOMAL PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPAR-GAMMA)EXPRESSION AND REDUCTION OF MMP-9 ACTIVITY THROUGH PPAR-GAMMA ACTIVATION IN MONONUCLEAR PHAGOCYTES IN-VITRO

Mononuclear phagocytes play an important role in atherosclerosis and i ts sequela plaque rupture in part by their secretion of matrix metallo proteinases (MMPs), including MMP-9. Peroxisomal proliferator-activate d receptor gamma (PPAR gamma), a transcription factor in the nuclear r eceptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-(Delta 12,14)-prostaglandin J(2) and th e antidiabetic agent troglitazone. The role of PPAR gamma in human ath erosclerosis 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 in creased 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 inhibite d 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 pr esent in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupt ure. PPAR gamma is likely to be an important regulator of monocyte/mac rophage function with relevance for human atherosclerotic disease.