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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:578.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development

Riikka Vikstedt; Dan Ye; Jari Metso; Reeni B. Hildebrand; Theo J.C. Van Berkel; Christian Ehnholm; Matti Jauhiainen; Miranda Van Eck

From National Public Health Institute (R.V., J.M., C.E., M.J.), Department of Molecular Medicine, Biomedicum, Helsinki, Finland; Division of Biopharmaceutics (D.Y., R.B.H. Th.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.

Correspondence to Miranda Van Eck, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9503, 2300 RA Leiden, The Netherlands. E-mail m.eck{at}lacdr.leidenuniv.nl

Objective— Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic lesion development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown.

Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP^–/–) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP^–M/–M) resulted in a 29% (P<0.01 for difference in lesion area) reduction in aortic root lesion area as compared with mice possessing functional macrophage PLTP (384±36*10³ µm² in the PLTP^–M/–M group (n=10), as compared with 539±35*10³ µm² in the PLTP^+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased lesion size in the PLTP^–M/–M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP^–M/–M group was 2-fold (P<0.001) lower than that in the PLTP^+M/+M group.

Conclusion— Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic lesion development in low-density lipoprotein receptor knockout mice on Western-type diet.

Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic lesion development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP^–/–) mice into irradiated low-density lipoprotein receptor knockout mice. Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic lesion development in low-density lipoprotein receptor knockout mice on Western-type diet.

Key Words: apolipoproteins • atherosclerosis • lipid transfer proteins • macrophages • mouse models

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