Lipid oxidation and nitration products as activators of cytoprotective Nrf2 signaling in the endothelium
Year: 2012
Type: dissertation
Abstract: Electrophilic products of lipid oxidation and nitration such as oxidized 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC) and nitro-fatty acids are potent signaling molecules in the vascular system.Electrophiles not only contribute to disease pathology but can also function as mediators of cytoprotective responses.The Keap1-Nrf2-ARE signaling pathway regulates a wide variety of antioxidant enzymes in response to oxidative stress or electrophilic stimuli.Upon activation, the inhibitor protein Keap1 is modified allowing the activation of transcription factor Nrf2 and the subsequent production of antioxidant enzymes.The aim of this thesis was to investigate the cytoprotective pathways activated by oxPAPC and nitro-oleic acid (OA-NO2), focusing on Nrf2 signaling.Both lipids were found to induce the expression of antioxidant enzymes in human primary endothelial cells, and oxPAPC also in murine arteries, in Nrf2-dependent manner.In addition, epoxyisoprostane and hydroperoxide phospholipids (PEIPC and PAPCOOH, respectively) were identified as the Nrf2 activating species in oxPAPC and furthermore, the electrophilic sn-2 side chain in the phospholipids appeared to be critical for activation of Nrf2 target genes.Genome-wide analysis of Nrf2-dependent and -independent effects of OA-NO2 on gene expression in human endothelial cells revealed that in addition to Nrf2, OA-NO2 also induced another signaling pathway, the heat shock response.These two pathways worked independently of each other and may both serve as mediators of the cytoprotective effects of OA-NO2 in the vasculature.Furthermore, OA-NO2 robustly upregulated the endothelin receptor B (ETB), a receptor involved in blood pressure control, via Nrf2.The molecular mechanism by which OA-NO2 activated Nrf2 involved a modification of Keap1 cysteines C38, C226, C273, C288, and C489.In contrast to several Nrf2 activators, Keap1 C151 was found not to be the sensor for OA-NO2 nor was it needed for the activation of Nrf2 in response to OA-NO2.The data suggests that OA-NO2 may share the activation mechanism with cyclopentanone prostaglandins using C273 or/and C288 in Keap1 as a sensor for Nrf2 activation.These results demonstrate that in addition to exerting potentially pathological effects, lipid oxidation and nitration products can be protective signaling mediators in the vascular system, and may confer protection against the early events leading to vascular diseases.
Author: Emilia Kansanen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Itä-Suomen Yliopisto
OpenAlex ID: W3095252039