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

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.