HDL and ApoA prevent cell death of endothelial cells induced by oxidized LDL.
We have previously demonstrated that toxic doses of mildly oxidized LDL evokes in cultured cells a delayed and sustained rise of cytosolic [Ca2+], eliciting in turn irreversible cell damage and leading finally to cell death. HDL and delipidated apolipoprotein (apo). A prevented effectively the toxic effect of oxidized LDL to bovine aortic endothelial cells, in a time- and dose-dependent manner. The major part of the protective effect was mimicked by purified apoA-I, whereas purified apoA-II exhibited only very low protective activity. The protective effect was independent of the paraoxonase-linked HDL activity. The protective effect of HDL is independent of the contact of HDL with oxidized LDL, as shown by preincubation of oxidized LDL with HDL or apoA. In contrast, the protective effect was dependent on the integrity of apoA and on the contact of HDL with cells, thus suggesting that HDL acts directly on cells by enhancing their resistance against oxidized LDL. Preincubation experiments show that the protective effect is dependent on the duration of the contact of cells with HDL (maximal effect observed after 12 to 16 hours' preincubation), is also dependent on protein synthesis, and is persistent for at least 48 hours after the end of the contact of HDL with cells. Finally, effective concentrations of HDL inhibit the Ca2+ peak, which is directly involved in the cytotoxic effect of oxidized LDL, as shown by the inhibitory effect of Ca2+ chelators. All together, these results suggest that HDL, mainly apoA-I, increases the resistance of endothelial cells against oxidized LDL and prevents its toxic (apoptotic) effect by blocking the pathogenic intracellular signaling (culminating in sustained Ca2+ rise) involved in cell death.
Suc
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Department of Biochemistry, INSERM U.466, IFR Louis Bugnard, University Paul Sabatier, Toulouse, France.
Escargueil-Blanc
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Troly
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Salvayre
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Nègre-Salvayre
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A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001054:Apolipoproteins A / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D043303:Aryldialkylphosphatase; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004950:Esterases / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity*
D001054:Apolipoproteins A; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D004950:Esterases; D043303:Aryldialkylphosphatase; D002118:Calcium