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.
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
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: