O39	Anti-inflammatory properties of Ramiprilat: reduction of monocyte adhesion to angiotensin II-stimulated endothelium is associated with AT1 downregulation.
3O.Soehnlein, 2A.Schmeisser, 3L.Lindbom, 1W.G.Daniel, 1Chr.D.Garlichs
1Medical Clinic II, University of Erlangen, Erlangen, DE; 2Heart Centre Dresden, University of Dresden, Dresden, DE; 3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE.

Objective: Because of the involvement of alternative pathways in the local AngII-formation, Angiotensin converting enzyme (ACE) inhibitors do not block the production of angiotensin II (AngII) in human arteries completely. Nevertheless, the anti-inflammatory properties of ACE-inhibitors are in many respects superior to those of AT1-antagonists. Therefore, our study focuses on the presumed modulation of local AngII-mediated inflammatory actions by ACE-inhibitors through a mechanism independent of blocking the AngII-formation. Methods: HUVEC were stimulated in vitro with 1µM AngII and when necessary pre-treated with 1µM ramiprilat (ACE-inhibitor), 1µM losartan (AT1-antagonist), or 1µM PD123.319 (AT2-antagonist). Adhesion molecule expression (P-selectin, VCAM-1, ICAM-1) was analysed by FACS. Monocyte adhesion to HUVEC was explored in flow chamber assays. To investigate NF-κB activation, nuclear extracts of activated HUVEC were stained for p65 and analysed by FACS. Expression of AT1 receptor was analysed by FACS and by Western blotting. Results: AngII induced upregulation of P-selectin, VCAM-1 and ICAM-1 on EC via activation of AT1, which was associated with enhanced monocyte adhesion in flow chamber assays. Both enhanced adhesion and adhesion molecule expression were significantly reduced by pre-treatment with ramiprilat. Ramiprilat reduced AT1 expression on EC and decreased the AngII-induced p65 translocation into the nucleus. Diminished AT1 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. Conclusion: Besides their well-known function as blockers of the AngII-formation ACE-inhibitors may locally modulate inflammatory processes by interfering with the expression of AT1. This may at least in part contribute to the benefits of ACE-inhibition in the treatment of atherosclerotic diseases.

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