MMP-9 Inhibition by ACE Inhibitor Reduces Oxidized LDL-Mediated Foam-Cell Formation

DOI 被引用文献2件 参考文献33件
  • Kojima Chiari
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University. Department of Internal Medicine IV, Tokyo Women's Medical University.
  • Ino Jun
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University. Department of Internal Medicine IV, Tokyo Women's Medical University.
  • Ishii Hideto
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.
  • Nitta Kosaku
    Department of Internal Medicine IV, Tokyo Women's Medical University.
  • Yoshida Masayuki
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.

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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.<BR>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.<BR>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.

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