Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment

• Published in: Circulation (New York, N.Y.) N.Y.), 2005-07, Vol.112 (4), p.578-586
• Main Authors: HELLER, Eric A, LIU, Emerson, FREEMAN, Mason W, MOORE, Kathryn J, LUSTER, Andrew D, GERSZTEN, Robert E, TAGER, Andrew M, SINHA, Sumita, ROBERTS, Jesse D, KOEHN, Stephanie L, LIBBY, Peter, AIKAWA, Elena Rabkin, JI QIU CHEN, HUANG, Paul
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - physiology; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Movement; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Immunohistochemistry; Leukotriene B4 - pharmacology; Medical sciences; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - cytology; Receptors, CCR2; Receptors, Chemokine - physiology; Receptors, Leukotriene B4 - deficiency; Receptors, Leukotriene B4 - physiology; Receptors, Purinergic P2 - deficiency; Receptors, Purinergic P2 - physiology; Signal Transduction; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.105.545616

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. 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. 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.