Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 66; no. 6; pp. 1220 - 1226
• Main Authors: Akhtar, Shamima, Hartmann, Petra, Karshovska, Ela, Rinderknecht, Fatuma-Ayaan, Subramanian, Pallavi, Gremse, Felix, Grommes, Jochen, Jacobs, Michael, Kiessling, Fabian, Weber, Christian, Steffens, Sabine, Schober, Andreas
• Format: Journal Article
• Language: English
• Published: United States 01.12.2015
• Subjects: 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; atherosclerosis; microRNAs; endothelial cells; chemokines
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.115.05886

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 Hif1 a 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.