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Titolo:
A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes
Autore:
Suzuki, T; Miyauchi, T;
Indirizzi:
Univ Tsukuba, Inst Clin Med, Dept Internal Med, Div Cardiovasc, Tsukuba, Ibaraki 3058575, Japan Univ Tsukuba Tsukuba Ibaraki Japan 3058575 sukuba, Ibaraki 3058575, Japan
Titolo Testata:
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
fascicolo: 5, volume: 280, anno: 2001,
pagine: R1399 - R1406
SICI:
0363-6119(200105)280:5<R1399:ANPAOE>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
CONGESTIVE-HEART-FAILURE; RAT CARDIAC MYOCYTES; MANGANESE SUPEROXIDE-DISMUTASE; PROTEIN-KINASE-C; A RECEPTOR ANTAGONISM; SERUM-FREE MEDIUM; PLASMA ENDOTHELIN-1; PULMONARY-HYPERTENSION; VENTRICULAR MYOCYTES; ENDOGENOUS ENDOTHELIN-1;
Keywords:
cultured cardiomyocytes; antioxidant; endothelin type A-receptor antagonist; protein kinase C; antisense oligodeoxyribonucleotide;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
64
Recensione:
Indirizzi per estratti:
Indirizzo: Suzuki, T Univ Tokyo, Grad Sch Med, Radiat Res Inst, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan Univ Tokyo 7-3-1 Hongo Tokyo Japan 1130033 Tokyo 1130033, Japan
Citazione:
T. Suzuki e T. Miyauchi, "A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes", AM J P-REG, 280(5), 2001, pp. R1399-R1406

Abstract

We previously reported that cardiomyocytes produce endothelin (ET)-1 and that the tissue level of ET-1 markedly increased in failing hearts in rats with chronic heart failure. Because the level of plasma ET-1 also increased progressively in patients with breast cancer who received doxorubicin (Dox;Adriamycin), which possesses cardiotoxicity, we hypothesized that ET-1 plays a role in the pathophysiology of cardiomyocytes injured by Dox. In this study, we investigated the effect of ET-1 on the cytotoxicity of Dox in primary cultured neonatal rat cardiomyocytes. The results showed that ET-1 effectively attenuated Dox-induced acute cardiomyocyte cytotoxicity (24-h incubation with Dox) evaluated by in vitro cell toxicity assay {3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase release}. The cytoprotective effect of ET-1 was mediated via ETA receptors, because pretreatment with the ETA-receptor antagonist BQ123 completely suppressed the cytoprotective effect of ET-1, whereas the ETB-receptor antagonist BQ788 did not. The cytoprotective effect of ET-1 was abolished by pretreatment with cycloheximide or staurosporine. These results suggest that a protein molecule(s), which is synthesized de novo by the stimulation of protein kinase pathway, is involved in the cytoprotective effect of ET-1. ET-1 increased the expression of an endogenous antioxidant, manganese superoxide dismutase (Mn-SOD), in the cardiomyocytes, as demonstrated by a Western blotting analysis. Pretreatment with an antisense oligodeoxyribonucleotide of Mn-SOD markedly attenuated the cytoprotective effect of ET-1 on the Dox-induced cytotoxicity. However, under conditions of prolonged incubation with Dox (48 h), ET-1 did not affect Dox-induced cardiomyocyte cytotoxicity in culture. These results suggest that ET-1 prevents the early phase of Dox-induced cytotoxicity via the upregulation of the antioxidant Mn-SOD through ETA receptors in cultured cardiomyocytes.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 08:33:20