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

Shamima Akhtar, Petra Hartmann, Ela Karshovska, Fatuma-Ayaan Rinderknecht, Pallavi Subramanian, Felix Gremse, Jochen Grommes, Michael Jacobs, Fabian Kiessling, Christian Weber, Sabine Steffens, Andreas Schober*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

91 Citations (Web of Science)

Abstract

Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1 is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1 in atherosclerosis is unclear. HIF-1 was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1 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-1 expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1-induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein-stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1 expression in ECs by mildly oxidized low-density lipoprotein-derived unsaturated lysophosphatidic acid. Endothelial HIF-1 promoted atherosclerosis by triggering miR-19a-mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1/miR-19a pathway may be a therapeutic option against atherosclerosis.
Original languageEnglish
Pages (from-to)1220-1226
JournalHypertension
Volume66
Issue number6
DOIs
Publication statusPublished - Dec 2015

Keywords

  • atherosclerosis
  • chemokines
  • endothelial cells
  • microRNAs

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