The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE−/− mice

• LTB4 induces proinflammatory signaling in atherosclerosis through BLT receptors.
• The BLT receptor antagonist BIIL284 reduced atherosclerosis in ApoE−/− mice.
• Atherosclerotic lesion smooth muscle cell content was decreased by BIIL284.
• BIIL284-tretaed mice exhibited less arterial MMP activities and lower plasma cytokines.
• BLT receptor antagonism may be of therapeutic value in atherosclerosis.

Leukotriene B4 (LTB4) induces proinflammatory signaling through BLT receptors expressed in atherosclerotic lesions. Either genetic or pharmacological targeting of the high affinity LTB4 receptor, BLT1, reduces atherosclerosis in different mouse models. The low affinity BLT2 receptor for LTB4 may transduce additional pro-atherogenic signaling, but combined BLT1 and BLT2 receptor antagonism has not previously been explored in atherosclerosis. The aim of the present study was to unravel the effects of the BLT receptor antagonist BIIL284 in apolipoprotein E deficient mice in terms of atherosclerotic lesion size and composition, as well as on arterial matrixmetalloproteinase (MMP) activity and plasma cytokines. Oral administration of BIIL284 (0.3–3 mg/kg) dose-dependently decreased atherosclerotic lesion size after 12 weeks. In addition, significantly smaller aortic lesions were observed in mice treated with BIIL284 (3 mg/kg) for 24 weeks. The reduced atherosclerosis was associated with less lesion smooth muscle cells, less arterial MMP activities and lower plasma levels of TNF-α and IL-6. Taken together, these results suggest a therapeutic value of BLT receptor antagonism in atherosclerosis.