Investigating the Role of Endothelial Glycogen Synthase Kinase3α/β in Atherogenesis in Low Density Lipoprotein Receptor Knockout Mice

Risk factors for developing cardiovascular disease (CVD) are associated with inflammation and endothelial activation. Activated endothelial cells (ECs) express adhesion proteins that recruit monocytes to the subendothelial layer initiating plaque development. Understanding the mechanism(s) by which ECs increase adhesion protein expression will facilitate the development of therapies aimed at preventing CVD progression and mortality. Glycogen synthase kinase (GSK)3 alpha/beta are constitutively active kinases which have been associated with many cellular pathways regulating cell viability and metabolism. While roles for myeloid GSK3 alpha/beta in the development of atherosclerosis have been established, there is limited knowledge on the potential roles of endothelial GSK3 alpha/beta. With the use of Cre recombinase technology, GSK3 alpha/beta was knocked out of both ECs and macrophages (Tie2Cre GSK3 alpha/beta(fl/fl) LDLR-/-). A bone marrow transplant was used to replenish GSK3 alpha/beta in the myeloid lineage allowing the assessment of an endothelial-selective GSK3 alpha/beta knockout (BMT Tie2Cre GSK3 alpha/beta(fl/fl) LDLR-/-). In both models, adhesion protein expression, macrophage recruitment and plaque volume were reduced in GSK3 alpha knockout mice. GSK3 beta knockout had no significant effect. Results from this study are the first to suggest a pro-atherogenic role of endothelial GSK3 alpha and support existing evidence for targeting GSK3 alpha in the treatment of atherosclerotic CVD.