title: Importance of intracellular angiotensin II in vascular smooth muscle cell apoptosis: inhibition by the angiotensin AT1 receptor antagonist irbesartan.
abstract: The intracellular uptake of Angiotensin II has been described, although its physiological role is not yet understood. We aimed to study the role of Angiotensin II internalization in Angiotensin II-induced apoptosis. Vascular smooth muscle cells were cultured from male Wistar-Kyoto rats and treated with Angiotensin II (1 microM, 48 h). Apoptosis was assessed by DNA fragmentation, cell cytometry and caspase-3 activity. The Angiotensin AT(1) receptor antagonist irbesartan (0.1-10 microM) and the inhibitors of Angiotensin II internalization phenylarsine oxide (PAO, 20 microM), but not the AT(2) receptor antagonist PD123319 (S-(+)-1-[(4-(Dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid di(trifluoroacetate) salt), decreased Angiotensin II-mediated apoptosis. Pre-treatment with irbesartan, but not with PD123319, blocked Angiotensin II internalization. We found a strong correlation between intracellular Angiotensin II staining and Angiotensin II-induced apoptosis for all compared groups. We therefore conclude that internalization of Angiotensin II is involved in apoptosis of vascular smooth muscle cells induced by this peptide.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Av. Complutense, s/n. 28040 Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ruiz
authors.forename: Santiago
authors.initials: S
authors.lastname: Redondo
authors.forename: Eugenia
authors.initials: E
authors.lastname: Padilla
authors.forename: Antonio
authors.initials: A
authors.lastname: Gordillo-Moscoso
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.forename: Gloria
authors.initials: G
authors.lastname: Balfagón
authors.forename: Teresa
authors.initials: T
authors.lastname: Tejerina
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001152:Arsenicals / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014162:Transfection
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001152:Arsenicals; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C029341:oxophenylarsine; D000804:Angiotensin II; C073402:PD 123319; D053148:Caspase 3; D000077405:Irbesartan