Plasma Phospholipid Transfer Protein Deficiency in Mice Is Associated With a Reduced Thrombotic Response to Acute Intravascular Oxidative Stress

Abstract

Objective-Earlier in vitro studies suggested a putative role for the plasma phospholipid transfer protein (PLTP) in the modulation of blood coagulation. The effect of PLTP expression on blood coagulation under both basal and oxidative stress conditions was compared here in wild-type and PLTP-deficient (PLTPϪ/Ϫ) mice. Methods and Results-Under basal conditions, PLTP deficiency was associated with an extended tail bleeding time despite a significant depletion of vascular ␣-tocopherol content and an impairment of endothelial function. When acute oxidative stress was generated in vivo in the brain vasculature, the steady state levels of oxidized lipid derivatives, the extent of blood vessel occlusion, and the volume of ischemic lesions were more severe in wild-type than in PLTPϪ/Ϫ mice. Conclusion-In addition to its recognized hyperlipidemic, proinflammatory, and proatherogenic properties, PLTP increases blood coagulation and worsens the extent of ischemic lesions in response to acute oxidative stress. Thus, PLTP arises here as a cardiovascular risk factor for the late thrombotic events occurring in the acute phase of atherosclerosis. Key Words: blood coagulation Ⅲ endothelial function Ⅲ lipids Ⅲ thrombosis Ⅲ vascular biology P lasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, unesterified cholesterol, diacylglycerides, lipopolysaccharides, and vitamin E. It has been implicated in several biological processes, including the production and catabolism of very-low-density and low-density lipoproteins and the remodeling of high-density lipoproteins. Overall, PLTP expression was found to result in a higher incidence and faster progression of atherosclerosis in animal models, and increased expression of PLTP was most frequently associated with an increased risk of cardiovascular disease in humans. 1,2 These observations recently led to the emergence of pharmacological PLTP inhibitors as putative therapeutic tools in the prevention and treatment of cardiovascular disease. 3 Because of its hyperlipidemic and proinflammatory properties, PLTP increases the formation of fatty streaks and atherosclerotic lesions in the early, silent phase of the disease. In this context, the proatherogenicity of PLTP was mainly explained in terms of an increased production and reduced antioxidative protection of plasma apolipoprotein B-containing lipoproteins. 4 -6 In contrast, the implication of PLTP in the distal, thrombotic events of the disease (in particular the interaction between the hypercoagulable blood and the vascular wall ) has not yet been studied in vivo. Addressing the latter point is warranted by recent but contradictory sets of data that were obtained in vitro. On the one hand, PLTP was described as a putative factor in hypocoagulation because it has the ability in vitro (1) to favor the scavenging of anionic phospholipids (mainly phosphatidylserine [PS]), thus resulting in the attenuation of their procoagulant effect, 7 and (2) to prevent endotheliu...

Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis

“…Ten years ago, it was reported that PLTP KO mice exhibit a longer clotting time (tail bleeding) compared with WT mice and that this could be related to a relative decrease in PS externalization via a reduction in the vitamin E level in erythrocytes (74). Consistent with this result, Desrumaux et al (75) reported that plasma PLTP deficiency is associated with a reduced thrombotic response to acute intravascular oxidative stress. Thus, PLTP seems to be involved in hypercoagulation.…”

Mechanisms for the prevention of vitamin E excess

“…In all four backgrounds, the PLTP defi ciency increased oxidative damage ( 97 ). PLTP defi ciency also decreased ␣ -tocopherol concentrations in both the brain and the vascular wall, decreased hepatic ␣ -tocopherol concentrations, and led to an increase in apoB degradation ( 98 ).…”

Plasma PLTP (phospholipid-transfer protein): an emerging role in ‘reverse lipopolysaccharide transport’ and innate immunity

“…From LPS aggregates to HDL in vitro [14] From HDL to LDL in vitro [15] From bacterial blebs to HDL in vitro [16] From LPS aggregates to HDL in vivo [17] (b) Biochemical/biological pathways [38,39] Brain physiology [40] Reproductive biology [41] Reverse LPS transport Innate immunity [17] Cancer treatment [42] (apolipoprotein B)-containing lipoprotein production by the liver [23,25,26,45]. In addition, vitamin E redistribution between lipoproteins and the vascular wall could contribute to PLTP atherogenicity [13,43,46].…”