Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. Academic Article uri icon

Overview

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 alpha (TNF-alpha) 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 (AT(2)) receptor, as demonstrated by enhancement of MMP-1 production by an AT(2) agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT(2) 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 AT(2) agonist increased prostaglandin E(2) (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 AT(2) antagonist inhibited the PGE(2) production induced by TNF-alpha and GM-CSF. Ang II, through its interaction with the AT(2) receptor, has a central role in mediating the PGE(2)-dependent production of MMP-1 by monocytes stimulated with TNF-alpha 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.

publication date

  • April 7, 2005

Research

keywords

  • Angiotensin II
  • Coronary Artery Disease
  • Dinoprostone
  • Monocytes
  • Phosphoprotein Phosphatases
  • Receptor, Angiotensin, Type 2

Identity

Scopus Document Identifier

  • 22144445977

PubMed ID

  • 15817699

Additional Document Info

volume

  • 78

issue

  • 1