Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis

Background: Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerosis lesions, where it seems to be macrophage derived. The aim of the present study is to evaluate the atherogenic potential of macrophage derived PLTP. Methods and Findings: Here we show that macrophages from human PLTP transgenic mice secrete active PLTP. Subsequently, we performed bone marrow transplantations using either wild type mice (PLTPwt/wt), hemizygous PLTP transgenic mice (huPLTPtg/wt) or homozygous PLTP transgenic mice (huPLTPtg/tg) as donors and low density lipoprotein receptor deficient mice (LDLR-/-) as acceptors, in order to establish the role of PLTP expressed by bone marrow derived cells in diet-induced atherogenesis. Atherosclerosis was increased in the huPLTPtg/wt → LDLR-/ - mice (2.3-fold) and even further in the huPLTPtg/tg→LDLR-/ - mice (4.5-fold) compared with the control PLTPwt/wt→LDLR-/- mice (both P<0.001). Plasma PLTP activity levels and non-HDL cholesterol were increased and HDL cholesterol decreased compared with controls (all P<0.01). PLTP was present in atherosclerotic plaques in the mice as demonstrated by immunohistochemistry and appears to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice do not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages results in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages. Conclusions: We conclude that PLTP expression by bone marrow derived cells results in atherogenic effects on plasma lipids, increased PLTP activity, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size

The physiological role of lipoprotein (a)

Lipoprotein (a) (Lp(a)) is one of the most atherogenic lipoproteins, and, although we know plenty about the pathophysiology of Lp(a), its physiological function and metabolism remain elusive. From our previous results and more recent reports, the following model of Lp(a) metabolism emerges: apolipoprotein a (apo(a)) is biosynthesized in liver cells and the size of the isoform determines its rate of synthesis and excretion. In a first step, specific kringle IV domains in apo(a), mainly T-6 and T-7, bind to circulating low-density lipoproteins, followed by a second step in which stabilization of the newly formed Lip(a) complex is achieved by a disulfide bridge. Circulating Lp(a) interacts specifically with kidney cells, or possibly other tissues, causing cleavage of 2/3-3/4 of the N-terminal part of apo(a) by a collagenase-type protease. Part of these apo(a) fragments are found as excretory products of Lp(a) in urine, but there are indications that they, in fact, represent the biologically active form of apo(a) and are possibly responsible for the atherogenicity of Lp(a). Strategies for reducing this atherogenic lipoprotein with medication should, therefore, aim at interfering with either the assembly of Lp(a) or the stimulation of apo(a) fragmentation. (C) 2002 Prous Science, All rights reserved