期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 42, 期 2, 页码 241-252出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2009.10.002
关键词
ABCA1; Hypoxia; HIF-1; Macrophages; Atherosclerosis; Cholesterol efflux
资金
- German Research Foundation
- Fraunhofer Project Group Regensbug
- LipidomicNet [FP7-HEALTH 2007-2.1.1.6-202272]
ATP-binding cassette transporter A1 plays (ABCA1) a major role in reverse cholesterol transport, a process closely related to atherogenesis. In the thickening atherosclerotic lesions lipid loaded macrophages are exposed to regions of local hypoxia that may influence reverse cholesterol transport. Here we studied the effect of hypoxia on ABCA1 regulation and cholesterol efflux in human macrophages. We found that the hypoxia-inducible factor 1 (HIF-1) specifically binds to the HIF-1 response element of the ABCA1 promoter and the HIF-1 complex increases ABCA1 promoter activity along with ABCA1 expression. Primary human macrophages exposed to hypoxia or expressing constitutively active HIF-1 alpha responded with a potent change in ABCA1 expression, which showed a strong correlation with HIF-1 beta expression (r: 0.95-0.91). Moreover, ABCA1-mediated cholesterol efflux was also found to be regulated by HIF-1 beta under hypoxia. In vivo, in macrophages prepared from human atherosclerotic lesions ABCA1 levels showed a strong correlation with HIF-1 beta expression. This in vivo regulatory mechanism was confirmed in human pre-eclamptic placentas, a clinical condition with severe local hypoxia. These results demonstrate that HIF-1beta availability determines ABCA1 expression and cholesterol efflux in macrophages under hypoxia and may contribute to the interpersonal variability of atherosclerotic lesion progression. (C) 2009 Elsevier Ltd. All rights reserved.
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