Zusammenfassung
Background:
ATP-binding cassette transporter A1 (ABCA1) is a plasmamembrane protein that is primarily involved in high-density lipoprotein(HDL) production in liver cells and in the elimination of intracellularcholesterol in peripheral tissues. Functional deficiency of this protein leadsto low levels of circulating HDL, a clinical condition called Tangier’s disease. In peripheral tissues impaired ...
Zusammenfassung
Background:
ATP-binding cassette transporter A1 (ABCA1) is a plasmamembrane protein that is primarily involved in high-density lipoprotein(HDL) production in liver cells and in the elimination of intracellularcholesterol in peripheral tissues. Functional deficiency of this protein leadsto low levels of circulating HDL, a clinical condition called Tangier’s disease. In peripheral tissues impaired ABCA1 function may lead to localcholesterol accumulation.
Aim:
Atherosclerotic lesion associated lipid-loaded macrophages expressABCA1 as a primary reverse cholesterol transporter. These macrophagesare exposed to regions local hypoxia inside the lesions, which may have amajor impact on ABCA1 mediated reverse cholesterol transport. We studiedthe effect of hypoxia on ABCA1 regulation and cholesterol efflux in humanmacrophages.
Methods:
Primary human monocyte derived macrophages and hepato-cytes as well as monocytic and hepatocytic cell lines were cultivated invitro in order to analyze the binding of the hypoxia-inducible factor 1(HIF-1) complex to the ABCA1 promoter and to determine the ABCA1response to HIF-1 signaling in normoxic and hypoxic conditions. To evaluate the functional effect of hypoxia on ABCA1 mediated lipid effluxtotal cholesterol was measured from the culture media in hypoxic conditions and after transduction of the cells with constitutively active HIF-1alpha adenovirus construct. The results were confirmed in human suben-dothelial fat depositions and pre-eclamptic placentas.
Results:
We found that HIF-1 specifically binds to the HIF-1 responseelement of the ABCA1 promoter, and the HIF-1 complex increasesABCA1 promoter activity along with ABCA1 expression. Primary humanmacrophages exposed to hypoxia or expressing constitutively active HIF-1alpha respond with a potent change in ABCA1 expression, which showsa strong correlation with HIF-1beta expression (r 0.95–0.91). Moreover,ABCA1-mediated cholesterol efflux was also found to be regulated byHIF-1beta under hypoxia. In vivo, macrophages prepared from humanatherosclerotic lesions ABCA1 levels show a strong correlation with HIF-1beta expression. This in vivo regulatory mechanism was confirmed inhuman pre-eclamptic placentas, a clinical condition with severe localhypoxia.
Conclusions:
These results demonstrate that HIF-1beta availability deter-mines ABCA1 expression and cholesterol efflux in macrophages underhypoxia. The individually observed differences in HIF-1beta expression,therefore, may contribute to the interpersonal variability of atheroscleroticlesion progression. HIF-1beta as a potential drug target may open novelpathways for cardiovascular protection therapies.
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