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

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.

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 micromol/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.

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 antiinflamma-tory mechanism of imidaprilat in atherogenesis.