title: Renin-angiotensin system modulates oxidative stress-induced endothelial cell apoptosis in rats.
abstract: The role of the renin-angiotensin system in oxidative stress-induced apoptosis of endothelial cells (ECs) was investigated using a rat model and cultured ECs. EC apoptosis was induced by 5-minute intra-arterial treatment of a rat carotid artery with 0.01 mmol/L H2O2 and was evaluated at 24 hours by chromatin staining of en face specimens with Hoechst 33342. Although activity of angiotensin-converting enzyme in arterial homogenates was not increased, administration of an angiotensin-converting enzyme inhibitor temocapril for 3 days before H2O2 treatment inhibited EC apoptosis, followed by reduced neointimal formation 2 weeks later. Also, an angiotensin II type 1 (AT1) receptor blocker (olmesartan) inhibited EC apoptosis, whereas angiotensin II administration accelerated apoptosis independently of blood pressure. Next, cultured ECs derived from a bovine carotid artery were treated with H2O2 to induce apoptosis, as evaluated by DNA fragmentation. Combination of angiotensin II and H2O2 dose-dependently increased EC apoptosis and 8-isoprostane formation, a marker of oxidative stress. Conversely, temocapril and olmesartan reduced apoptosis and 8-isoprostane formation induced by H2O2, suggesting that endogenous angiotensin II interacts with H2O2 to elevate oxidative stress levels and EC apoptosis. Neither an AT2 receptor blocker, PD123319, affected H2O2-induced apoptosis, nor a NO synthase inhibitor, NG-nitro-L-arginine methyl ester, influenced the effect of temocapril on apoptosis in cell culture experiments. These results suggest that AT1 receptor signaling augments EC apoptosis in the process of oxidative stress-induced vascular injury.
authors.affiliation: Department of Geriatric Medicine, Kyorin University School of Medicine, Tokyo, Japan. akishita-tky@umin.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Akishita
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nagai
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Noriko
authors.initials: N
authors.lastname: Sudoh
authors.forename: Tokumitsu
authors.initials: T
authors.lastname: Watanabe
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
authors.forename: Koichi
authors.initials: K
authors.lastname: Kozaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Toba
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002339:Carotid Arteries / Q000201:enzymology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049673:History, 20th Century; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016877:Oxidants; D013777:Tetrazoles; D013841:Thiazepines; C055603:temocapril hydrochloride; C437965:olmesartan; D006861:Hydrogen Peroxide; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester