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


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 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.


CONCLUSIONS
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.
Kojima
Chiari
C
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Ino
Jun
J
Ishii
Hideto
H
Nitta
Kosaku
K
Yoshida
Masayuki
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D008077:Lipoproteins, LDL; D061965:Matrix Metalloproteinase Inhibitors; C495137:OLR1 protein, human; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C078006:imidaprilat