Low-density lipoproteins supply phospholipid-bound arachidonic acid for platelet eicosanoid production

Abstract

After the rapid extracorporal reduction of plasma low-density lipoprotein (LDL) by LDL apheresis, the percentages of arachidonic acid (AA)-containing species of phosphatidylcholine (PC) were lowered in the plasma of patients with hypercholesterolemia. The same PC species with AA were also decreased in the patient’s platelets. Thus the supply of phospholipid-bound AA from LDL to the platelets was probably diminished after the apheresis. We therefore analyzed the concentration dependence of the transfer of phospholipid-bound AA from LDL to the platelets under in vitro conditions. The amount of [14C]AA-PC transferred to platelets strongly increased upon elevation of LDL from 0.1 to 1 mg protein/ml, with a less marked elevation being noted at higher LDL concentrations. After stimulation with thrombin (0.5 U/ml), 7.1% ([14C]AA-PC) and 10.6% ([14C]AA-phosphatidylethanolamine) of the 14C transferred from LDL to the platelets were recovered in the eicosanoids [14C]thromboxane B2(TxB2) plus 12-[14C]hydroxyeicosatetraenoic acid. Experimental increases and reductions of the [14C]AA-PC import were associated with comparable modifications in the [14C]TxB2production of the platelets. Accordingly, the import of phospholipid-bound [14C]AA is a necessary prerequisite for the formation of14C-labeled eicosanoids. In summary, the transfer of phospholipids from LDL to the platelets markedly varies within the physiological range of lipoprotein concentrations. LDL contributes to platelet eicosanoid formation by supplying platelets with phospholipid-bound AA.

Conversion of Low Density Lipoprotein-associated Phosphatidylcholine to Triacylglycerol by Primary Hepatocytes

“…Hence, fatty acids at both the sn1 and sn2 positions of PC are utilized for TG synthesis. In this regard, it was shown that platelets can selectively internalize LDL phospholipids by an unknown receptor(s) and use them as a source of fatty acids, particularly arachidonic acid, which in turn is involved in the production of eicosanoids (32,34). It is noteworthy that platelets do not express LDLR (34).…”

Mechanisms for Antiplatelet Action of Statins

“…Among them the modifications of cholesterol content in platelet membranes with changes of fluidity and a relative COX-1 hyperactivity that may explain the increased urinary thromboxane levels has been clearly described [18,24]. Moreover a direct relation between cholesterolemia and antiport mechanisms such as Na + /H + exchange has been implicated in the alterations of platelet acidification seen with enhanced platelet reactivity [20].…”

“…Indeed platelet hyperactivity, which is a key step in atherothrombosis [9,10], has been described in hypercholesterolemic [11][12][13][14][15][16] and atherosclerosis prone subjects [9,10,17]. Concerning hypercholesterolemia platelet hyperreactivity could be due to several mechanisms related with LDL-C such as membrane composition and antiport mechanisms and/or specific intracellular signalling pathways and biological activities [18][19][20][21][22][23][24]. Furthermore oxidized-LDL, either in hypercholesterolemic or normolipemic subjects, has been reported to activate platelets by eNOS downregulation, NO bioavailability modification, *Address correspondence to this author at the Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Policlinico Le Scotte, University of Siena, V.le Bracci, 53100, Siena, Italy; Tel: +39(0)577585741; Fax: +39(0577)44114; E-mail: puccetti@unisi.it altered Ca-ATPase function, and syk tyrosine and rho kinases stimulation [25][26][27][28].…”

Lipidomic analysis of platelet senescence

“…LDL sensitizes PLTs via receptor‐mediated signaling and lipid exchange 16 . Related to these findings, LDL also directly contributes to the formation of PLT eicosanoids by supplying arachidonic acid either phospholipid bound or free 20 …”