Abstract
AimsAtherosclerosis is a public health concern affecting many worldwide, but its pathogenesis remains unclear. In this study we investigated the role of IKKε during the formation of atherosclerosis and its molecular mechanism in the mouse aortic vessel wall.Methods and ResultsC57BL/6 wild-type or IKKε knockout mice bred into the ApoE knockout genetic background were divided into 4 groups: (1) wild-type (WT), (2) ApoE knockout (AK), (3) IKKε knockout (IK), (4) or both ApoE and IKKε knockout (DK). Each group of mice were fed with a high fat diet (HFD) for 12 weeks from 8 weeks of age. Immunohistochemistry and Western blotting analysis demonstrated obvious increases in the expression of IKKε in the AK group compared with the WT group, especially in the intima. Serum lipid levels were significantly higher in the AK and DK groups than in the other two groups. Staining with hematoxylin-eosin and Oil Red, as well as scanning electron microscopy revealed less severe atherosclerotic lesions in the DK group than in the AK group. Immunofluorescence and Western blot analysis demonstrated obvious increases in the expression of NF-κB pathway components and downstream factors in the AK group, especially in the intima, while these increases were blocked in the DK group.ConclusionThe knockout of IKKε prevented significant atherosclerosis lesions in the mouse aorta from in both wild-type and ApoE knockout mice fed a HFD, suggesting that IKKε may play a vital role in HFD-induced atherosclerosis and would be an important target for the treatment of atherosclerosis.
Highlights
Atherosclerosis, a progressive pathological disorder underlying cardiovascular diseases, is the major cause of mortality and morbidity in industrialized societies and is characterized by a large number of risk factors with multiple pathogenesis hypotheses [1,2]
The knockout of IKKe prevented significant atherosclerosis lesions in the mouse aorta from in both wild-type and ApoE knockout mice fed a high fat diet (HFD), suggesting that IKKe may play a vital role in HFD-induced atherosclerosis and would be an important target for the treatment of atherosclerosis
A surprising increase in the expression of IKKe was first discovered in the ApoE knockout (AK) group compared with the WT group through the application of Western blot analysis (Figure 1A-B)
Summary
Atherosclerosis, a progressive pathological disorder underlying cardiovascular diseases, is the major cause of mortality and morbidity in industrialized societies and is characterized by a large number of risk factors with multiple pathogenesis hypotheses [1,2]. The initiation and progression of atherosclerosis have been attributed to a chronic inflammatory process due to high fat diet (HFD)-induced lipid accumulation in the subendothelial space and lipid peroxidation-promoted endothelial cell activation. Activated endotheial cells modulate the expression of many different cell adhesion molecules, chemotactic factors and proinflammatory cytokines, which contribute to the recruitment and migration of both monocytes and smooth muscle cells in the vessel wall [3,4,5,6,7]. The activation of NF-kB is modulated by the IkB kinase (IKK) complex.
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