Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment.
BACKGROUND
It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB4), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB(4) signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown.


RESULTS
To directly assess the role of the LTB4-BLT1 pathway in atherogenesis, we bred BLT1(-/-) mice into the atherosclerosis-susceptible apoE(-/-) strain. Compound-deficient apoE(-/-)/Blt1(-/-) mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE(-/-) controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1(+/+) SMCs and absent in Blt1(-/-) cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions.


CONCLUSIONS
These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.
Heller
Eric A
EA
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, East-8307, 149 13th St, Charlestown, MA 02129, USA.
Liu
Emerson
E
Tager
Andrew M
AM
Sinha
Sumita
S
Roberts
Jesse D
JD
Koehn
Stephanie L
SL
Libby
Peter
P
Aikawa
Elena Rabkin
ER
Chen
Ji Qiu
JQ
Huang
Paul
P
Freeman
Mason W
MW
Moore
Kathryn J
KJ
Luster
Andrew D
AD
Gerszten
Robert E
RE
D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D002465:Cell Movement; D007150:Immunohistochemistry; D007975:Leukotriene B4 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction
D001057:Apolipoproteins E; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C513240:LTB4R protein, human; C503704:Ltb4r1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018102:Receptors, Leukotriene B4; D018048:Receptors, Purinergic P2; D007975:Leukotriene B4