Hypertension (Dallas, Tex. 1979), 2015-12, Vol.66 (6), p.1220-1226
2015
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- Autor(en) / Beteiligte
- Titel
- Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a
- Ist Teil von
- Hypertension (Dallas, Tex. 1979), 2015-12, Vol.66 (6), p.1220-1226
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0194-911XeISSN: 1524-4563DOI: 10.1161/HYPERTENSIONAHA.115.05886Titel-ID: cdi_proquest_miscellaneous_1733188765
- Format
- –
- Schlagworte
- Animals, Atherosclerosis - genetics, Atherosclerosis - metabolism, Blotting, Western, Cell Adhesion - drug effects, Cell Adhesion - genetics, Cells, Cultured, Chemokine CCL2 - genetics, Chemokine CCL2 - metabolism, Chemokine CXCL1 - genetics, Chemokine CXCL1 - metabolism, Endothelial Cells - drug effects, Endothelial Cells - metabolism, Gene Expression - drug effects, Humans, Hypoxia-Inducible Factor 1, alpha Subunit - genetics, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Lipoproteins, LDL - pharmacology, Mice, Knockout, MicroRNAs - genetics, Monocytes - metabolism, Oligonucleotides, Antisense - genetics, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference