| First Author | Akhtar S | Year | 2015 |
| Journal | Hypertension | Volume | 66 |
| Issue | 6 | Pages | 1220-6 |
| PubMed ID | 26483345 | Mgi Jnum | J:298194 |
| Mgi Id | MGI:6477426 | Doi | 10.1161/HYPERTENSIONAHA.115.05886 |
| Citation | Akhtar S, et al. (2015) Endothelial Hypoxia-Inducible Factor-1alpha Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a. Hypertension 66(6):1220-6 |
| abstractText | Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1alpha is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1alpha in atherosclerosis is unclear. HIF-1alpha was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1alpha 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-1alpha expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1alpha-induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein-stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1alpha expression in ECs by mildly oxidized low-density lipoprotein-derived unsaturated lysophosphatidic acid. Endothelial HIF-1alpha promoted atherosclerosis by triggering miR-19a-mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1alpha/miR-19a pathway may be a therapeutic option against atherosclerosis. |
