Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 3, Pages 1124-1138Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx1155
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Funding
- Instrufoundation
- Finnish Cultural Foundation, North Savo Regional Fund
- Emil Aaltonen Foundation
- Finnish Foundation for Cardiovascular Research
- Aarne and Aili Turunen Foundation
- Maud Kuistila Memorial Foundation
- Antti and Tyyne Soininen Foundation
- Aarne Koskelo Foundation
- Saara Kuusisto and Salme Pennanen Foundation
- Ida Montin Foundation
- Kuopio University Foundation
- Orion-Farmos Research Foundation
- Finnish Funding Agency for Technology and Innovation
- European Regional Development Fund
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Finnish Cancer Foundation
- Academy of Finland [287478, 275147]
- Academy of Finland
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Phospholipids, such as 1-palmitoyl-2-arachidonoyl-snglycero-3-phosphocholine (PAPC), are the major components of cell membranes. Their exposure to reactive oxygen species creates oxidized phospholipids, which predispose to the development of chronic inflammatory diseases and metabolic disorders through endothelial activation and dysfunction. Although the effects of oxidized PAPC (oxPAPC) on endothelial cells have been previously studied, the underlying molecular mechanisms evoking biological responses remain largely unknown. Here, we investigated the molecular mechanisms of oxPAPC function with a special emphasis on NRF2-regulated microRNAs (miRNAs) in human umbilical vein endothelial cells (HUVECs) utilizing miRNA profiling, global run-on sequencing (GRO-seq), genome-wide NRF2 binding model, and RNA sequencing (RNA-seq) with miRNA overexpression and silencing. We report that the central regulators of endothelial activity, KLF2 for quiescence, PFKFB3 for glycolysis, and VEGFA, FOXO1 and MYC for growth and proliferation, are regulated by transcription factor NRF2 and the NRF2-regulated miR-106b similar to 25 cluster member, miR-93, in HUVECs. Mechanistically, oxPAPC was found to induce glycolysis and proliferation NRF2-dependently, and oxPAPC-dependent induction of the miR-106b similar to 25 cluster was mediated by NRF2. Additionally, several regulatory loops were established between NRF2, miR-93 and the essential regulators of healthy endothelium, collectively implying that NRF2 controls the switch between the quiescent and the proliferative endothelial states together with miR-93.
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