BACKGROUND: Eicosapentaenoic acid (EPA), a major n-3 polyunsaturated fatty acid, is reported to have various protective effects for cardiovascular disease. However, few studies have focused on the influence of EPA on vascular calcification. METHODS AND RESULTS: Arterial medial calcification (AMC) was induced by administering warfarin (3 mg/g food) and vitamin K1 (1.5 mg/g food) for 2 weeks in Sprague-Dawley rats (control group), and EPA (1 g/kg/day) was administered for 2 weeks simultaneously with warfarin and vitamin K1 (EPA group) or after initiation of AMC (late EPA group). EPA showed a marked reduction of medial calcification in the EPA group, and showed a similar effect in the late EPA group. Immunohistochemical and RT-PCR analyses showed that EPA lowered the expression of osteogenetic markers, such as osteopontin, alkaline phosphatase and core binding factor-α1 in the aorta. Significant migration of macrophages with expression of matrix-metalloproteinase (MMP)-2 or MMP-9 was observed in the aortic adventitia around calcification. EPA also reduced macrophage infiltration, MMP-9 expression as well as gene expression of monocyte chemotactic protein (MCP)-1. CONCLUSIONS: These observations indicate that EPA attenuates arterial medial calcification through an effect associated with the suppression of MMP-9 activity and inhibition of macrophage infiltration as well as osteogenic protein expression in warfarin-induced rat models.
BACKGROUND:Eicosapentaenoic acid (EPA), a major n-3 polyunsaturated fatty acid, is reported to have various protective effects for cardiovascular disease. However, few studies have focused on the influence of EPA on vascular calcification. METHODS AND RESULTS: Arterial medial calcification (AMC) was induced by administering warfarin (3 mg/g food) and vitamin K1 (1.5 mg/g food) for 2 weeks in Sprague-Dawley rats (control group), and EPA (1 g/kg/day) was administered for 2 weeks simultaneously with warfarin and vitamin K1 (EPA group) or after initiation of AMC (late EPA group). EPA showed a marked reduction of medial calcification in the EPA group, and showed a similar effect in the late EPA group. Immunohistochemical and RT-PCR analyses showed that EPA lowered the expression of osteogenetic markers, such as osteopontin, alkaline phosphatase and core binding factor-α1 in the aorta. Significant migration of macrophages with expression of matrix-metalloproteinase (MMP)-2 or MMP-9 was observed in the aortic adventitia around calcification. EPA also reduced macrophage infiltration, MMP-9 expression as well as gene expression of monocyte chemotactic protein (MCP)-1. CONCLUSIONS: These observations indicate that EPA attenuates arterial medial calcification through an effect associated with the suppression of MMP-9 activity and inhibition of macrophage infiltration as well as osteogenic protein expression in warfarin-induced rat models.