Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: Implications for atherosclerotic plaque rupture

Min P. Kim, Min Zhou, Larry M. Wahl

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Angiotensin II (Ang II)-mediated hypertension increases the risk for acute coronary syndrome, a consequence of atherosclerotic plaque rupture, which may be caused by matrix metalloproteinases (MMPs). Here, we show that human primary monocytes stimulated with tumor necrosis factor α (TNF-α) and granulocyte macrophage-colony stimulating factor (GM-CSF) release Ang II, which is an integral component of the signal transduction pathway that leads to MMP-1 production. An Ang II-mediated increase in MMP-1 synthesis occurred only in conjunction with cytokine stimulation. Moreover, Ang II mediated its effect through the Ang II type 2 (AT2) receptor, as demonstrated by enhancement of MMP-1 production by an AT2 agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT2 antagonist. Additionally, exogenous Ang II caused a significant enhancement in MMP-1 production by cytokine-stimulated monocytes, and the most effective enhancement occurrred when Ang II was added 6 h after stimulation. Furthermore, Ang II and the AT2 agonist increased prostaglandin E2 (PGE 2), which in turn mediated the increase in MMP-1, as shown by the inhibition of MMP-1 by indomethacin or aspirin. In contrast, the AT2 antagonist inhibited the PGE2 production induced by TNF-α and GM-CSF. Ang II, through its interaction with the AT2 receptor, has a central role in mediating the PGE2-dependent production of MMP-1 by monocytes stimulated with TNF-α and GM-CSF. These observations provide insight into the association between hypertension and acute coronary syndrome and a possible mechanism by which Ang-converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.

Original languageEnglish (US)
Pages (from-to)195-201
Number of pages7
JournalJournal of Leukocyte Biology
Volume78
Issue number1
DOIs
StatePublished - Jul 2005

Keywords

  • Angiotensin II receptor subtype 2
  • Cytokines
  • Inflammation

ASJC Scopus subject areas

  • Cell Biology

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