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. LTB₄ 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. Methods and 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.