ACE inhibition lowers angiotensin-II-induced monocyte adhesion to HUVEC by reduction of p65 translocation and AT 1 expression.
Angiotensin-converting enzyme (ACE) inhibitors interfere with several key events of vascular inflammation resulting in impressive reductions in coronary vascular events. However, in human arteries ACE inhibitors block the production of angiotensin II (AngII) incompletely because of the involvement of alternative pathways in local AngII formation. Therefore, our study concentrated on the presumed modulation by ACE inhibition of local AngII-mediated inflammatory actions by a mechanism independent of blockage of AngII formation. We analyzed the effect of the ACE inhibitor ramiprilat on AngII-dependent cell adhesion molecule (CAM) expression and adhesion of monocytic THP-1 cells to endothelial cells. AngII induced upregulation of P-selectin, VCAM-1 and ICAM-1 on endothelial cells via activation of AT 1, which was correlated with enhanced THP-1 adhesion in flow chamber assays. Both enhanced adhesion and adhesion molecule expression were significantly reduced by pretreatment with ramiprilat. Ramiprilat reduced AT 1 expression on endothelial cells and decreased the AngII-induced p65 translocation into the nucleus. Diminished AT 1 expression and adhesion molecule expression in response to ramiprilat treatment were partially reversed after incubation with a bradykinin 2 receptor antagonist, suggesting that elevated bradykinin levels under ACE inhibition may be involved in the beneficial effect of ACE inhibitors. Thus, modulation of the local AngII system by ramiprilat may at least in part contribute to the benefits of ACE inhibition in the treatment of atherosclerotic diseases.
Soehnlein
Oliver
O
Medical Clinic II, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany. Oliver.Sohnlein@fyfa.ki.se
Schmeisser
Alexander
A
Cicha
Iwona
I
Reiss
Christine
C
Ulbrich
Holger
H
Lindbom
Lennart
L
Daniel
Werner G
WG
Garlichs
Christoph D
CD
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051996:Transcription Factor RelA; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; C052549:ramiprilat; C065679:icatibant; D017257:Ramipril; D001920:Bradykinin