HIF-1beta determines ABCA1 expression under hypoxia in human macrophages

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• 作者：Peter Ugocsai ; Antonia Hohenstatt ; Gyö ; rgy Paragh ; Gerhard Liebisch ; Thomas Langmann ; Zsuzsanna Wolf ; Thomas Weiss ; Peter Groitl ; Thomas Dobner ; Piotr Kasprzak ; Lá ; szló ; Gö ; bö ; l&#x
• 关键词：ABCA1 ; Hypoxia ; HIF-1 ; Macrophages ; Atherosclerosis ; Cholesterol efflux
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2010
• 出版时间：February 2010
• 年：2010
• 卷：42
• 期：2
• 页码：241-252
• 全文大小：1326 K

文摘

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-1alpha responded with a potent change in ABCA1 expression, which showed a strong correlation with HIF-1beta expression (r: 0.95–0.91). Moreover, ABCA1-mediated cholesterol efflux was also found to be regulated by HIF-1beta under hypoxia. In vivo, in macrophages prepared from human atherosclerotic lesions ABCA1 levels showed a strong correlation with HIF-1beta 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.