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FASEB J. 2012 Feb;26(2):927-37. doi: 10.1096/fj.11-191593. Epub 2011 Oct 31.

Activated platelets contribute to oxidized low-density lipoproteins and dysfunctional high-density lipoproteins through a phospholipase A2-dependent mechanism.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM)/Université de Bourgogne, Lipids, Nutrition, Cancer, Faculté de Médecine, Dijon, France. dblache@u-bourgogne.fr

Abstract

Plasma activity of secretory phospholipase A2 (sPLA2) increases in patients with cardiovascular disease. The present study investigated whether platelet-released sPLA2 induces low-density lipoprotein (LDL) and high-density lipoprotein (HDL) modifications that translate into changes in lipoprotein function. Activated but not resting platelets induced oxidative modifications of human native LDLs and HDLs, which render these particles dysfunctional. Platelet-incubated LDLs stimulated the incorporation of cholesterol oleate into macrophages, and modified HDLs lost their cholesterol efflux capacity and antioxidant properties. In vitro and ex vivo experiments showed that lysophophatidylcholine accumulated in the platelet-modified LDLs and HDLs of mice expressing sPLA2 (Balb/c and transgenic C57Bl/6 mice expressing human sPLA2) but not in the lipoproteins of naturally sPLA2-deficient mice (C57Bl/6). Unlike C57Bl/6 mice, Balb/c mice injected with leptin (67 μg/mouse, i.p.) as an in vivo prothrombotic agent displayed increased plasma sPLA2 activity, reduced clotting time, higher plasma levels of oxidation products, increased production of nonesterified fatty acids, and more substantial platelet-mediated modification of lipoproteins. These effects were blocked completely by injection of the platelet inhibitor ticlopidine (5 mg/kg, i.p.) or by a sPLA2 inhibitor (LY311727, 3 mg/kg, i.p.). These results demonstrate that stimulated platelets are major contributors to plasma sPLA2 activity in vivo and account to a large extent for the adverse modification of circulating lipoproteins.

PMID:
22042222
DOI:
10.1096/fj.11-191593
[Indexed for MEDLINE]

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