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

AbstractAIM:
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 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.
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 antiinflamma-tory mechanism of imidaprilat in atherogenesis.
AuthorsChiari Kojima, Jun Ino, Hideto Ishii, Kosaku Nitta, Masayuki Yoshida
JournalJournal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 17 Issue 1 Pg. 97-105 (Feb 2010) ISSN: 1880-3873 [Electronic] Japan
PMID20093780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazolidines
  • Lipoproteins, LDL
  • Matrix Metalloproteinase Inhibitors
  • OLR1 protein, human
  • RNA, Small Interfering
  • Scavenger Receptors, Class A
  • Scavenger Receptors, Class E
  • oxidized low density lipoprotein
  • imidaprilat
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
Topics
  • Angiotensin-Converting Enzyme Inhibitors (pharmacology)
  • Cell Line
  • Enzyme Activation (drug effects)
  • Foam Cells (cytology, drug effects, metabolism)
  • Humans
  • Imidazolidines (pharmacology)
  • Lipoproteins, LDL (metabolism)
  • Matrix Metalloproteinase 2 (metabolism)
  • Matrix Metalloproteinase 9 (genetics, metabolism)
  • Matrix Metalloproteinase Inhibitors
  • Mitogen-Activated Protein Kinases (metabolism)
  • Monocytes (cytology, drug effects, metabolism)
  • RNA, Small Interfering
  • Scavenger Receptors, Class A (metabolism)
  • Scavenger Receptors, Class E (metabolism)

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