Abstract
ObjectiveOxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2.Methods and ResultsBoth magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages.ConclusionOur results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis.
Highlights
Atherosclerosis is the principal cause of coronary artery disease, cerebrovascular accidents and gangrene of the extremities
Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model
Chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages
Summary
Atherosclerosis is the principal cause of coronary artery disease, cerebrovascular accidents and gangrene of the extremities. There is a consensus that atherosclerotic lesions result from an excessive, inflammatory-fibro-proliferative response to various forms of insult to the endothelium and smooth muscle of the arterial wall. As a critical component of inflammatory responses, oxidative stress has been shown to mediate vascular damage in several classic risk factors for atherosclerosis, such as hypertension [1], dyslipidemia [2], and obesity [2]. Its activation has been shown to protect endothelial cells from oxidant injury [5], suppresses smooth muscle cell proliferation [6], and reduce arterial pro-inflammatory state [7], suggesting that Nrf may have an anti-atherosclerotic function. Myeloid deletion of Nrf markedly reduces atherosclerosis [11], suggesting that the role of Nrf in atherosclerosis is cell type-dependent and further investigations are warranted. A recent study showed that dietary Nrf activators inhibit atherogenic processes [12], supporting that Nrf pathway is an anti-atherosclerotic target
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