Hyperactivated monocytes and lipid laden macrophages are frequently detected in diabetes and hypertension, and contribute to the progression of vascular complications. We have previously demonstrated that the binding of an ACE inhibitor to ACE in endothelial cells results in the phosphorylation of the enzyme on Ser1270 within its cytoplasmic tail, followed by the activation of the c-Jun N-terminal kinase (JNK)/c-Jun, an increase in AP-1 binding and changes in the expression of ACE and cyclooxygenase-2. Here we determined whether ACE signalling occurs in monocytes. ACE protein was expressed at low levels in freshly isolated human monocytes and levels were increased by up to 6 fold after 4 days in culture. Treatment of 4 day old monocytes with ramiprilat, stimulated JNK activity indicating that ACE signalling occurs in these cells. As ramiprilat delays the onset of type II diabetes in humans we assessed the ability of the ACE inhibitor to regulate PPAR[gamma] in ACE expressing monocytes.Ramiprilat elicited the nuclear accumulation of PPAR[gamma] and upregulated the expression of resistin (2.1-fold) and the cholesterol transporter ABCA1 (2.3-fold) at the mRNA level. Our data indicate that ACE inhibitors can activate JNK in human monocytes which in turn interfere with signalling via PPAR[gamma].