Hnin Hnin Aung, Robin Altman, Tun Nyunt, Jeffrey Kim, Saivageethi Nuthikattu, Madhu Budamagunta, John C Voss, Dennis Wilson, John C Rutledge, Amparo C Villablanca

Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment. Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRL lipolysis products) or a high-fat Western diet 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 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 pro-inflammatory, stress response, and oxidative stress genes, and activation of pro-apoptotic cascades. Male apolipoprotein E knockout mice were fed a high-fat/high-cholesterol Western diet for two months and brain microvessels isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hyppocampus and cerebellar brain region of the Western diet-fed animals compared to chow-fed control animals. 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 vascular cognitive impairment.