Inhibitory mechanisms of low concentrations of oxidized low-density lipoprotein on platelet aggregation.
The 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 microg/ml) inhibited platelet aggregation in human platelet-rich plasma stimulated by agonists. Moreover, oxLDL (40 and 80 microg/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 microg/ml) in phosphorus-32-labeled platelets. In addition, oxLDL (40 and 80 microg/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 microg/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.
Chou
Duen-Suey
DS
Graduate Institute of Medical Sciences, Taipei Medical University, Taiwan, ROC.
Chan
Chih-Hsiang
CH
Hsiao
George
G
Shen
Ming-Yi
MY
Tsai
Yan-Jyu
YJ
Chen
Tzeng-Fu
TF
Sheu
Joen-Rong
JR
D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D004161:Diphenylhexatriene / Q000737:chemistry; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D039661:Integrin beta3 / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D039661:Integrin beta3; D008077:Lipoproteins, LDL; D008840:Microfilament Proteins; D010750:Phosphoproteins; D040201:Platelet Membrane Glycoprotein IIb; C099252:oxidized low density lipoprotein; D000098662:Vasodilator-Stimulated Phosphoprotein; D004161:Diphenylhexatriene; D003094:Collagen; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D013917:Thrombin; D002118:Calcium