Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice

Abstract

Abstract-Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr Ϫ/Ϫ ) mice and apolipoprotein E deficient (apoE Ϫ/Ϫ ) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE Ϫ/Ϫ mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE Ϫ/Ϫ mice at all time points tested. Lesion area reduction was also demonstrated in LDLr Ϫ/Ϫ mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1 Key Words: leukotriene B4 Ⅲ atherosclerosis Ⅲ monocyte chemoattractant protein-1 T he pathogenesis of atherosclerosis is a complex process, which involves the recruitment and activation of monocytes in the developing atherosclerotic lesion. 1 It is thought to initiate when circulating monocytes are first attracted to a site of vascular injury through the upregulation of adhesion molecules and chemotactic factors in the lesion. 2,3 Once attached to the vessel wall, monocytes, attracted by a gradient of chemotactic factors, migrate between the endothelial cells into the subendothelial space where they differentiate into macrophages and become lipid-laden foam cells. 2 A growing body of evidence suggests that the recruitment of monocytes is governed by cell-specific chemoattractants. Several molecules have chemotactic activity for monocytes, including N-formylmethionyl peptides exemplified by N-formylmethionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, the arachidonic acid metabolite leukotriene B4 (LTB4), 12-hydroxyeicosatetraenoic acid (12-HETE), and the chemoattractant monocyte chemotactic protein-1 (MCP-1). 4See page 361 and cover MCP-1 is the prototype of the CC chemokine ␤ subfamily and exhibits the most potent chemotactic activity for monocytes. 5 MCP-1 is highly expressed in human atheromatous plaques, 6 and its overexpression contributes to the development of atherosclerosis in mouse models. 7 In hypercholesterolemic mice, a deficiency in either MCP-1 8 or the MCP-1 receptor (CCR2) 9 results in a marked decrease in atheromas and fewer monocytes in vascular lesions. However, at later stages of lesion development in these mice, differences in lesion size relative to wild type become less pronounced. These data suggest that other chemotactic factors are likely compensating for the lack of MCP-1.LTB4, a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, is also a potent chemoattractant and proinflammatory mediator thought to be involved in the pathogenesis of several ...

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

“…A 5-LO promoter variant is associated with abnormal carotid artery intima-media thickness and heightened inflammatory biomarkers 30 . In addition, antagonists of LTB4 block the development of atherosclerosis in apo-E-deficient and LDRLdeficient mice 31 , and a congenic mouse strain with a heterozygous deficiency of 5-LO shows resistance to atherosclerosis 16 , further supporting the idea that greater activity of the 5-LO pathway has a role in predisposition to atherosclerosis.…”

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

“…For example, we demonstrated that deficiency of the gene encoding 5-lipoxygenase (Alox5) in mice protects against the development of aortic lesions [3,4], and that promoter variants of the human ALOX5 gene are associated with increased carotid intima-media thickness [5]. Other groups have also reported findings that support the involvement of the 5-LO/LT pathway in CVD traits [6][7][8][9][10][11][12][13].…”

Leukotriene Signaling in Atherosclerosis and Ischemia

“…2 The potential involvement of leukotrienes in the different stages of the atherosclerosis process eventually leading to cerebral and myocardial ischemia. Abbreviations: SMC smooth muscle cells, MMP matrix metalloproteinase, I/R ischemia and reperfusion protein E (ApoE) knockout mice in which either genetic or pharmacological targeting of the BLT 1 receptor reduces lipid accumulation and foam cell infiltration [36][37][38].…”

“…2) [10]. The chemoattractant activity induced by LTB 4 through BLT 1 and BLT 2 receptors expressed on monocytes may play an important role in the continued accumulation of macrophages at the site of the initial foam cell infiltration [36]. Since macrophages represent a major source of 5-LO in the cardiovascular system, LTB 4 -induced monocyte recruitment could potentially further exacerbate the inflammatory activity at sites of atherosclerotic lesions.…”