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. 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.
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. 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 humanatherosclerotic 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.
Authors: Richard C Li; Bodduluri Haribabu; Steven P Mathis; Jinkwan Kim; David Gozal Journal: Am J Respir Crit Care Med Date: 2011-04-14 Impact factor: 21.405
Authors: Magnus Bäck; De-xiu Bu; Robert Bränström; Yuri Sheikine; Zhong-Qun Yan; Göran K Hansson Journal: Proc Natl Acad Sci U S A Date: 2005-11-17 Impact factor: 11.205