Abstract
Background: Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. Leukotrines are involved in different stages of atherosclerosis. Therefore this study was undertaken to evaluate the effect of montelukast and zileuton on the progression of atherosclerosis. Materials and methods: Thirty-five male rabbits were used in this study. These animals randomized into 5 groups (7 rabbits each). Rabbits in first group were maintained on normal rabbit chow diet and used as normal diet control group (NC). While the rabbits in other four groups were fed on atherogenic diet (2% cholesterol) for 8 weeks. The second group, Atherogenic Control Group (AC) rabbits received atherogenic diet alone. Third group, Positive Control Group (PC) rabbits received atherogenic diet and ethanol as vehicle. Forth group, Montelukast Treated Group (MT) rabbits received montelukast 1.5 mg per kg daily and the fifth group, Zileuton Treated Group (ZT) rabbits received zileuton 150 mg per kg daily. At the end of 8th weeks animals were sacrificed, blood sample was collected to measure the following parameters: lipid profile, plasma GSH, MDA, and hsCRP. Immunohistochemical analysis (VCAM-1, MCP-1, TNF-α, and IL17) and histopathologic assessment of aortic atherosclerotic changes were also performed. Results: Compared to NC, levels of lipid profile, atherogenic index, hsCRP, and MDA are increased while GSH were decreased in animals on atherogenic diet (p<0.001). There was statistically insignificant difference in the study parameters between positive control groups, when compared with those on atherogenic diet. Immunohistochemical analysis showed that expression of aortic VCAM-1, MCP-1, TNF-α and IL17 were significantly increased in AC group compared to NC group (p<0.001). Histopathologic finding showed that animals on atherogenic diet have significant atherosclerotic lesion compared to NC group. Compared to AC group both montelukast and zileuton do not have significant effect on lipid profile. Montelukast and zileuton cause statistically significant reduction in hsCRP and MDA, (p<0.001). Montelukast and zileuton treatment caused statistically significant, increase in plasma levels of GSH and reduced plasma MDA level (p<0.001). Both montelukast and zileuton treatment significantly reduced the expression of aortic VCAM-1, MCP-1, TNF-α and IL17 (p<0.001). Histopathologic examination of aortic arch showed that both montelukast and zileuton significantly reduced atherosclerotic lesion (p<0.001). Conclusion: Both montelukast and zileuton reduce lipid peroxidation, systemic inflammation and aortic expressions of inflammatory markers used in this study and reduced the progression of atherosclerosis.
Highlights
Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall, this buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs [1]
In metabolic disorders associated with atherosclerosis as hypercholesterolemia, hypertension, and diabetes mellitus, a reduced endothelium-mediated, NO-dependent vasodilation is observed, which may contribute to the initiation and progression of atherosclerosis associated with these disorders [3]
Concerning hsCRP this study showed that montelukast treatment significantly reduces plasma hsCRP compared to Atherogenic Control Group (AC) group
Summary
Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall, this buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs [1]. Hypercholesterolemia enhances the response to vasoconstrictor agonists and attenuates endothelium-dependent relaxation in isolated vessels and in vivo. EDNO is recognized to inhibit several pathologic processes that are critical to the development of atherosclerosis. These include monocyte adherence and chemotaxis, platelet adherence and aggregation, and vascular smooth muscle proliferation [2]. In metabolic disorders associated with atherosclerosis as hypercholesterolemia, hypertension, and diabetes mellitus, a reduced endothelium-mediated, NO-dependent vasodilation is observed, which may contribute to the initiation and progression of atherosclerosis associated with these disorders [3]. Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. This study was undertaken to evaluate the effect of montelukast and zileuton on the progression of atherosclerosis
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