Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

Felecia M Marottoli; Troy N Trevino; Xue Geng; Zarema Arbieva; Pinal Kanabar; Mark Maienschein-Cline; James C Lee; Sarah E Lutz; Leon M Tai

doi:10.3389/fcell.2021.668296

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

Front Cell Dev Biol. 2021 Jun 10:9:668296. doi: 10.3389/fcell.2021.668296. eCollection 2021.

Authors

Felecia M Marottoli¹, Troy N Trevino¹, Xue Geng², Zarema Arbieva³, Pinal Kanabar⁴, Mark Maienschein-Cline⁴, James C Lee², Sarah E Lutz¹, Leon M Tai¹

Affiliations

¹ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States.
² Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, United States.
³ Genome Research Core, Research Resources Center, University of Illinois at Chicago, Chicago, IL, United States.
⁴ Research Informatics Core, Research Resources Center, University of Illinois at Chicago, Chicago, IL, United States.

Abstract

Reports of APOE4-associated neurovascular dysfunction during aging and in neurodegenerative disorders has led to ongoing research to identify underlying mechanisms. In this study, we focused on whether the APOE genotype of brain endothelial cells modulates their own phenotype. We utilized a modified primary mouse brain endothelial cell isolation protocol that enabled us to perform experiments without subculture. Through initial characterization we found, that compared to APOE3, APOE4 brain endothelial cells produce less apolipoprotein E (apoE) and have altered metabolic and inflammatory gene expression profiles. Further analysis revealed APOE4 brain endothelial cultures have higher preference for oxidative phosphorylation over glycolysis and, accordingly, higher markers of mitochondrial activity. Mitochondrial activity generates reactive oxygen species, and, with APOE4, there were higher mitochondrial superoxide levels, lower levels of antioxidants related to heme and glutathione and higher markers/outcomes of oxidative damage to proteins and lipids. In parallel, or resulting from reactive oxygen species, there was greater inflammation in APOE4 brain endothelial cells including higher chemokine levels and immune cell adhesion under basal conditions and after low-dose lipopolysaccharide (LPS) treatment. In addition, paracellular permeability was higher in APOE4 brain endothelial cells in basal conditions and after high-dose LPS treatment. Finally, we found that a nuclear receptor Rev-Erb agonist, SR9009, improved functional metabolic markers, lowered inflammation and modulated paracellular permeability at baseline and following LPS treatment in APOE4 brain endothelial cells. Together, our data suggest that autocrine signaling of apoE in brain endothelial cells represents a novel cellular mechanism for how APOE regulates neurovascular function.

Keywords: SR9009; apolipoprotein E; brain endothelial cells; inflammation; metabolism.

Abstract

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