Beschreibung:
<jats:p>
Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1α is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1α in atherosclerosis is unclear. HIF-1α was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1α in atherosclerosis, deletion of the
<jats:italic>Hif1</jats:italic>
a gene was induced in ECs from apolipoprotein E knockout mice (EC-
<jats:italic>Hif1a</jats:italic>
<jats:sup>
<jats:italic>−/−</jats:italic>
</jats:sup>
) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC-
<jats:italic>Hif1a</jats:italic>
<jats:sup>
<jats:italic>−/−</jats:italic>
</jats:sup>
compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC-
<jats:italic>Hif1a</jats:italic>
<jats:sup>
<jats:italic>−/−</jats:italic>
</jats:sup>
mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1α expression. Moreover, endothelial
<jats:italic>Hif1a</jats:italic>
deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1α–induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein–stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1α expression in ECs by mildly oxidized low-density lipoprotein–derived unsaturated lysophosphatidic acid. Endothelial HIF-1α promoted atherosclerosis by triggering miR-19a–mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1α/miR-19a pathway may be a therapeutic option against atherosclerosis.
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