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From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Published: December 2015
AI Article Synopsis
Article Abstract
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 Hif1a gene was induced in ECs from apolipoprotein E knockout mice (EC-Hif1a(-/-)) 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-Hif1a(-/-) compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC-Hif1a(-/-) 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 Hif1a 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.
