Macrophage phospholipid transfer protein contributes significantly to total plasma phospholipid transfer activity and its deficiency leads to diminished atherosclerotic lesion development.
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.


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*10(3) microm2 in the PLTP(-M/-M) group (n=10), as compared with 539+/-35*10(3) microm2 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.


CONCLUSIONS
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.
Vikstedt
Riikka
R
National Public Health Institute, Department of Molecular Medicine, Biomedicum, Helsinki, Finland.
Ye
Dan
D
Metso
Jari
J
Hildebrand
Reeni B
RB
Van Berkel
Theo J C
TJ
Ehnholm
Christian
C
Jauhiainen
Matti
M
Van Eck
Miranda
M
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000503:physiopathology*; D001693:Biological Transport, Active / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D010743:Phospholipids / Q000502:physiology*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity
D016632:Apolipoprotein A-I; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D012333:RNA, Messenger; D011973:Receptors, LDL