期刊
ATHEROSCLEROSIS
卷 219, 期 1, 页码 40-48出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2011.07.010
关键词
8-Dihydroxy-3-methyl-isochromanone (XJP-1); Lipopolysaccharide (LPS); Nitric oxide (NO); Tumor necrosis factor-alpha (TNF-alpha); Monocyte chemotactic protein (MCP)-1; Cell adhesion molecules; Endothelin-1 (ET-1); Mitogen-activated protein kinases (MAPKs); Nuclear factor-kappa B (NF-kappa B)
资金
- National Natural Science Fund [308731144]
Aim: We investigated whether 8-dihydroxy-3-methyl-isochromanone (XJP-1), a novel angiotensin-converting enzyme inhibitor (ACEI), exhibited inhibitory activity to lipopolysaccharide (LPS)-accelerated vascular inflammation. Methods: Human umbilical vein endothelial cells (HUVECs) were isolated from human umbilical cords and cultured. The direct effect of XJP-1 on the activation of endothelial cells was measured using MTT assay. Nitric oxide (NO) in the culture medium was measured using Griess method. The expression of cell adhesion molecules (ICAM-1 and VCAM-1) was determined by flow cytometry and RT-PCR. The protein expression levels of tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein (MCP)-1, and endothelin-1 (ET-1) secretion were measured using ELISA. Quantitative analysis of eNOS, iNOS, inhibitory factor NF-kappa B (I kappa B) and MAPKs were determined using Western blot analysis. The translocation of NF-kappa B from the cytoplasm to the nucleus was determined using immunofluorescence. Results: XJP-1 significantly inhibited LPS-mediated endothelial cell dysfunction, as measured by NO production, iNOS expression, adhesion molecule (ICAM-1, VCAM-1) expression, and chemokine (TNF-alpha, MCP-1) production in vitro. It up-regulated eNOS expression in the same experimental setting. XJP-1 alone was found non-cytotoxic at the concentration up to 1000 mu M. The mechanistic investigations of XJP-1 suppression LPS-induced inflammation in HUVECs revealed that XJP-1 blocked NF-kappa B nuclear entry in an I kappa B-dependent manner, as well as inhibited MAPK activation induced by LPS. XJP-1 reduced endothelin-1 secretion and increased nitric oxide metabolite production by HUVECs. However, the effect of XJP-1 on nitric oxide and endothelin-1 metabolite production is mediated by the activation of bradykinin B-2 receptor being counteracted, at least in part, by a specific antagonist. Conclusion: XJP-1 inhibited LPS-induced cytotoxicity and inflammatory response. The mechanism underlying this protective effect might be related to the inhibition of MAPK and NF-kappa B signaling pathway activation, suggesting the potential inhibition of the atherosclerotic process by suppressing the expression of chemoattractant molecules and monocyte adhesion. XJP-1 also has an effect in improving endothelin-1 through activating bradykinin B-2 receptor. These findings indicated that XJP-1 is potentially a novel therapeutic candidate for the treatment of atherosclerosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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