Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms.
OBJECTIVE
Leukotriene B4 (LTB4), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB4 modulates atherosclerosis in cell lines expressing LTB4 receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1+/+ and BLT-1-/- mice.


RESULTS
Analysis of global changes in gene expression induced by LTB4 in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2, which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E-/- mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB4 receptor, BLT-2, and exhibited chemotaxis to LTB4.


CONCLUSIONS
The effects of LTB4 in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB4 promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation.
Subbarao
Krishnaprasad
K
James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202, USA.
Jala
Venkatakrishna R
VR
Mathis
Steven
S
Suttles
Jill
J
Zacharias
Wolfgang
W
Ahamed
Jasimuddin
J
Ali
Hydar
H
Tseng
Michael T
MT
Haribabu
Bodduluri
B
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D003433:Crosses, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007975:Leukotriene B4 / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
D001057:Apolipoproteins E; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C412377:leukotriene B2 receptor