Abstract 1199: Elevated Macrophage Expression of Phospholipid Transfer Protein Causes Atherosclerosis
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 atherosclerotic lesions, where it seems to be macrophage derived. We found 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 macrophage derived PLTP in atherogenesis. After feeding the animals a Western-type diet, 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 appeared to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice did not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages resulted in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages. In vivo, we found a marked induction in plasma PLTP activity upon treatment with thioglycolate. We conclude that PLTP expression by macrophages results in atherogenic effects on plasma lipids, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size.