title: Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways.
abstract: Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment (VCI). Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRLs; TGRL lipolysis products) or a high-fat Western diet (WD) suggests similar mechanisms may be present in brain microvascular endothelium. We investigated the hypothesis that TGRL lipolysis products cause lipotoxic injury to brain microvascular endothelium by generating increased mitochondrial superoxide radical generation, upregulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways, and activation of cellular oxidative stress and apoptotic pathways. Human brain microvascular endothelial cells were treated with human TGRL lipolysis products that induced intracellular lipid droplet formation, mitochondrial superoxide generation, ATF3-dependent transcription of proinflammatory, stress response, and oxidative stress genes, as well as activation of proapoptotic cascades. Male apoE knockout mice were fed a high-fat/high-cholesterol WD for 2 months, and brain microvessels were isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hippocampus and cerebellar brain region of the WD-fed animals compared with chow-fed control animals. The microvascular injury phenotypes observed in vitro and in vivo were similar. ATF3 plays an important role in mediating brain microvascular responses to acute and chronic lipotoxic injury and may be an important preventative and therapeutic target for endothelial dysfunction in VCI.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: Hnin Hnin
authors.initials: HH
authors.lastname: Aung
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: Robin
authors.initials: R
authors.lastname: Altman
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: Tun
authors.initials: T
authors.lastname: Nyunt
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: Saivageethi
authors.initials: S
authors.lastname: Nuthikattu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine.
authors.forename: Madhu
authors.initials: M
authors.lastname: Budamagunta
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine.
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine.
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine School of Medicine avillablanca@ucdavis.edu.
authors.forename: Amparo C
authors.initials: AC
authors.lastname: Villablanca
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002531:Cerebellum / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020214:Cerebrovascular Trauma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D066273:Diet, Western / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008074:Lipoproteins / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D008074:Lipoproteins; D014280:Triglycerides; C030087:lipoprotein triglyceride
keywords: cell signaling; cerebrovascular circulation; diet and dietary lipids; endothelial cells; gene expression; inflammation; lipolysis; mitochondria; reactive oxygen species; triglyceride-rich lipoproteins