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Titolo:
Mechanisms underlying endothelial dysfunction in diabetes mellitus
Autore:
Hink, U; Li, HG; Mollnau, H; Oelze, M; Matheis, E; Hartmann, M; Skatchkov, M; Thaiss, F; Stahl, RAK; Warnholtz, A; Meinertz, T; Griendling, K; Harrison, DG; Forstermann, U; Munzel, T;
Indirizzi:
Univ Hamburg, Krankenhaus Eppendorf, Abt Kardiol, D-20246 Hamburg, GermanyUniv Hamburg Hamburg Germany D-20246 t Kardiol, D-20246 Hamburg, Germany Emory Univ, Div Cardiol, Atlanta, GA 30322 USA Emory Univ Atlanta GA USA 30322 Univ, Div Cardiol, Atlanta, GA 30322 USA Univ Mainz, Dept Pharmacol, D-6500 Mainz, Germany Univ Mainz Mainz Germany D-6500 z, Dept Pharmacol, D-6500 Mainz, Germany
Titolo Testata:
CIRCULATION RESEARCH
fascicolo: 2, volume: 88, anno: 2001,
pagine: E14 - E22
SICI:
0009-7330(20010202)88:2<E14:MUEDID>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITRIC-OXIDE SYNTHASE; PROTEIN-KINASE-C; SUPEROXIDE PRODUCTION; NADPH OXIDASE; DEPENDENT VASODILATION; VASCULAR TISSUE; SMOOTH-MUSCLE; L-ARGININE; ACTIVATION; TETRAHYDROBIOPTERIN;
Keywords:
diabetes; nitric oxide synthase; protein kinase C; uncoupling; NADPH oxidase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Munzel, T Univ Hamburg, Krankenhaus Eppendorf, Abt Kardiol, Martinistr 52,D-20246 Hamburg, Germany Univ Hamburg Martinistr 52 Hamburg Germany D-20246 urg, Germany
Citazione:
U. Hink et al., "Mechanisms underlying endothelial dysfunction in diabetes mellitus", CIRCUL RES, 88(2), 2001, pp. E14-E22

Abstract

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabeteswas induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N-G-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 07:54:29