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

Abstract

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)3α/β are constitutively active kinases which have been associated with many cellular pathways regulating cell viability and metabolism. While roles for myeloid GSK3α/β in the development of atherosclerosis have been established, there is limited knowledge on the potential roles of endothelial GSK3α/β. With the use of Cre recombinase technology, GSK3α/β was knocked out of both ECs and macrophages (Tie2Cre GSK3α/βfl/fl LDLR−/−). A bone marrow transplant was used to replenish GSK3α/β in the myeloid lineage allowing the assessment of an endothelial-selective GSK3α/β knockout (BMT Tie2Cre GSK3α/βfl/fl LDLR−/−). In both models, adhesion protein expression, macrophage recruitment and plaque volume were reduced in GSK3α knockout mice. GSK3β knockout had no significant effect. Results from this study are the first to suggest a pro-atherogenic role of endothelial GSK3α and support existing evidence for targeting GSK3α in the treatment of atherosclerotic CVD.

Glycogen synthase kinase 3 activity enhances liver inflammation in MASH

“…46 In another murine atherosclerosis model, deletion of endothelial GSK3α, but not GSK3β, attenuated atherosclerosis, which was associated with reduced endothelial adhesion molecule expression and monocyte recruitment to the vascular wall. 47 Despite several similarities, one of the differences between this and the current study is that GSK3α-deleted endothelial cells had decreased expression of VCAM1 in vivo , whereas, in the current study, GSK3 inhibition reduced the expression of ICAM-1 in vitro and in vivo . This discrepancy might be secondary to the differences between vascular endothelial cells and LSECs, which are specialized fenestrated endothelial cells.…”

GSK3 as a Master Regulator of Cellular Processes

“…Subsequent analyses revealed that the EC-specific KO of GSK3α had comparable effects to the dual-specific KO. Again, GSK3β KO mice showed no such changes, together indicating that the significant pro-atherogenic effect observed was exclusively mediated by endothelial GSK3α [19], which fits well with the beneficial outcome of whole body [21] or myeloid-specific GSK3α KO [22] described before.…”

“…Therefore, atherosclerosis mouse models with an endothelial-specific KO of GSK3α or β should be used. The respective Tie2Cre strains, however, exhibited dual-specific GSK3 KO in EC and macrophages [19], thus matching earlier reports on Tie2Cre-directed gene deletion in both lineages [20]. While most of the parameters analyzed (such as plasma lipids and body weight) showed no GSK3-dependent differences, EC/macrophage-specific GSK3α (but not GSK3β) KO mice were characterized by significantly reduced plaque volume, EC activation, and monocyte/macrophage recruitment when compared to age-matched controls.…”