Inhibitory mechanisms of low concentrations of oxidized low-density lipoprotein on platelet aggregation

Abstract

SummaryThe intracellular mechanisms underlying oxidized low-density lipoprotein (oxLDL)-signaling pathways in platelets are not yet completely understood. Therefore, the aim of this study was to further examine the effects of oxLDL in prevention of platelet aggregation. In this study, oxLDL concentration-dependently (40-120 lg/ml) inhibited platelet aggregation in human platelet-rich plasma stimulated by agonists. Moreover, oxLDL (40 and 80 lg/ml) markedly decreased the fluorescence intensity of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (150 nM). This phosphorylation was markedly inhibited by oxLDL (40 and 80 lg/ml) in phosphorus-32-labeled platelets. In addition, oxLDL (40 and 80 lg/ml) markedly increased levels of cyclic AMP and cyclic AMP-induced vasodilator-stimulated phosphoprotein (VASP) Ser 157 phosphorylation. The thrombin-evoked increase in pHi was inhibited in the presence of oxLDL (40 and 80 lg/ml). These results indicate that the antiplatelet activity of oxLDL may involve the following pathways. (1) oxLDL may initially induce conformational changes in platelet membranes, leading to inhibition of the activation of protein kinase C, followed by inhibition of P47 protein phosphorylation, and intracellular Ca 2+ mobilization. (2) oxLDL also activated formation of cyclic AMP and cyclic AMP-induced VASP Ser 157 phosphorylation, resulting in inhibition of the Na + /H + exchanger; this leads to reduced intracellular Ca 2+ mobilization, and ultimately to inhibition of platelet aggregation. This study further provides new insights concerning the effects of low concentrations of oxLDL on platelet aggregation.

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“…(b) oxLDL also activates formation of cyclic AMP and cyclic AMP-induced VASP Ser157 phosphorylation, resulting in inhibition of the Na + /H + exchanger; this leads to reduced intracellular Ca 2+ mobilization, and ultimately to inhibition of platelet aggregation. This study further provides new insights concerning the effects of low concentrations of oxLDL on platelet aggregation [15].…”

Highly oxidized low-density lipoprotein does not facilitate platelet aggregation

“… 2 , 11 – 13 However, some conflicting results have been reported as follows. 14 – 16 Using various concentrations (40–120 µg/mL) of oxLDL, low oxLDL concentrations were found to inhibit platelet aggregation. 14 Additionally, at a degree of oxidation of < 15%, oxLDL promoted platelet aggregation, but at > 30% oxidation, oxLDL attenuated platelet aggregation.…”

“… 14 – 16 Using various concentrations (40–120 µg/mL) of oxLDL, low oxLDL concentrations were found to inhibit platelet aggregation. 14 Additionally, at a degree of oxidation of < 15%, oxLDL promoted platelet aggregation, but at > 30% oxidation, oxLDL attenuated platelet aggregation. 15 These discrepancies between studies may be due to using different methods to oxidize LDL and to evaluate activation and aggregation of platelets, including the type of oxidant, LTA, and using platelet agonists.…”

“… 2 , 11 – 13 However, low oxLDL levels attenuate platelet function and aggregation in vitro . 14 – 16 These contradictions appear to stem from the heterogeneous nature of oxLDL, such as the oxidized domain and degree of oxidation.…”

Na+/H+ exchanger in the regulation of platelet activation and paradoxical effects of cariporide

“…The role of oxidized LDLs in inducing platelet aggregation, however, is unclear. Oxidized LDLs have been shown to increase platelet aggregation in some but not all studies, which may be due to different methodology in approaching oxidation, isolation, and concentrations (Chou et al, 2006). In some reports, highly oxidized LDLs failed to activate aggregation, whereas others have shown that mildly oxidized LDLs induced aggregation (Vlasova and Reznikova, 2000).…”