title: Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture.
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.
authors.affiliation: Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4352, USA.
authors.forename: Min P
authors.initials: MP
authors.lastname: Kim
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Larry M
authors.initials: LM
authors.lastname: Wahl
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000209:etiology; D009842:Oligopeptides / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C060894:CGP 42112A; C073402:PD 123319; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010749:Phosphoprotein Phosphatases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone