MMP-9 inhibition by ACE inhibitor reduces oxidized LDL-mediated foam-cell formation

Aim: angiotensin-converting enzyme inhibitors (aceis) have been shown to block matrix metalloproteinase (mmp)-9 activity,which plays a role in atherogenesis. mmp-9 activity of macrophages is increased during foam cell formation. to investigate the contribution of aceis to foam cell formation,we studied the effects of an acei,imidaprilat,on thp-1 macrophages and the underlying molecular mechanisms in vitro. methods and results: pre-treatment of thp-1 macrophages with imidaprilat (100 nmol/l,4 hours) significantly decreased foam cell formation induced by oxidized ldl (oxldl). imidaprilat reduced the protein level of mmp-9 in thp-1 macrophages and attenuated oxldl-induced mmp-9 activity in the culture supernatants. indeed,pretreatment of thp-1 macrophages with an mmp-2/9 inhibitor (20 μmol/l,4 hours) attenuated oxldl-induced foam-cell formation. imidaprilat or the mmp-2/9 inhibitor blocked oxldl-induced expressions of lox-1 and scavenger receptor-a (sr-a),but not that of cd36,in thp-1 macrophages. in addition,oxldl-induced activation of p38 mitogen-activated protein kinase (mapk) and erk,but not jnk,was blunted by imidaprilat or the mmp-2/9 inhibitor. finally,sirna against mmp-9 inhibited foam cell formation as well as lipid accumulation in thp-1 macrophages. conclusion: these findings suggest that imidaprilat reduces oxldl-triggered foam-cell formation in thp-1 macrophages via modulation of mmp-9 activity and may indicate a novel anti-inflammatory mechanism of imidaprilat in atherogenesis.