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Titolo:
SIMVASTATIN MODULATES THE HEAT-SHOCK RESPONSE AND CYTOTOXICITY MEDIATED BY OXIDIZED LDL IN CULTURED HUMAN ENDOTHELIAL SMOOTH-MUSCLE CELLS
Autore:
PIRILLO A; JACOVIELLO C; LONGONI C; RADAELLI A; CATAPANO AL;
Indirizzi:
UNIV MILAN,INST PHARMACOL SCI,VIA BALZARETTI 9 I-20133 MILAN ITALY UNIV MILAN,INST PHARMACOL SCI I-20133 MILAN ITALY UNIV MILAN,CTR STUDIO ATEROSCLEROSI I-20133 MILAN ITALY SAN RAFFAELE SCI INST,CARDIOVASC PHYSIOPATHOL LAB I-20132 MILAN ITALY
Titolo Testata:
Biochemical and biophysical research communications
fascicolo: 2, volume: 231, anno: 1997,
pagine: 437 - 441
SICI:
0006-291X(1997)231:2<437:SMTHRA>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; CHOLESTEROL; EXPRESSION; PROTEINS; GROWTH; INVITRO; INDUCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
37
Recensione:
Indirizzi per estratti:
Citazione:
A. Pirillo et al., "SIMVASTATIN MODULATES THE HEAT-SHOCK RESPONSE AND CYTOTOXICITY MEDIATED BY OXIDIZED LDL IN CULTURED HUMAN ENDOTHELIAL SMOOTH-MUSCLE CELLS", Biochemical and biophysical research communications, 231(2), 1997, pp. 437-441

Abstract

Oxidized low density lipoproteins (OxLDL) are toxic to cells of the arterial wall and trigger the expression of the inducible form of hsp70in cultured endothelial cells (EAhy-926) and smooth muscle cells (HUVSMC). The latter response is believed to protect cells hom toxicity since heat shock protein 70 (hsp70) is synthesized by cells under stresscondition to protect proteins from irreversible denaturation. Simvastatin (10(-8) M to 10(-5) M), a competitive inhibitor of hydroxy methylglutaryl coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthesis, enhanced the toxicity of OxLDL (300 mu g/mL) to endothelial cells and smooth muscle cells in a dose-dependent manner, as detected by H-3-adenine release and the MTT test. In EAhy, H-3-adenine release with OxLDL was 0.419+/-0.048 (ratio of radioactivity released in the medium to total radioactivity) versus 0.337+/-0.008 of control; in the presence of simvastatin and OxLDL this value increased from 0.49+/-0.01 at 10(-8) M to 0.918+/-0.001 at 10(-5) M with simvastatin alone (10(-5) M) this value was 0.463+/-0.025. Furthermore simvastatin reduced in a dose-dependent manner the expression of hsp70 triggered by OxLDL, as detected by immunoblotting. To address whether this finding was due to the effect of simvastatin on the cholesterol pathway, mevalonate (100 mu M) was used to bypass the HMG-CoA reductase block. This compound completely prevented the enhancement of OxLDL toxicityby simvastatin and restored the expression of hsp70. To verify whether cholesterol synthesis was required for the induction of hsp70 by OxLDL, squalestatin I (25 nM to 100 nM), an inhibitor off squalene synthase, another key enzyme of the cholesterol pathway, was used: OxLDL toxicity and hsp70 expression were not affected by this compound. These results indicate that simvastatin increases OxLDL cytotoxicity in vitrowith a concomitant decrease of hsp70 expression triggered by OxLDL and that the key step in the cholesterol synthesis responsible for theseeffects must be between mevalonate and squalene formation. (C) 1997 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 01:59:45