GSK3β Inhibition Ameliorates Atherosclerotic Calcification

Abstract

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3β (GSK3β) inhibition induced β-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3β inhibition or endothelial-specific deletion of GSK3β reduces atherosclerotic calcification. We also find that alterations in β-catenin and SMAD1 induced by GSK3β inhibition in the aortas of Apoe−/− mice are similar to Mgp−/− mice. Together, our results suggest that GSK3β inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp−/− mice.

Endothelial Reprogramming in Atherosclerosis

“…Epsins can bind ubiquitinated fibroblast growth factor receptor-1 (FGFR-1) through their ubiquitin-interacting motif (UIM), leading to the endocytosis and subsequent degradation of this receptor complex, which consequently significantly attenuates EndMT and the progression of AS [84]. GSK3β inhibition or the endothelial-specific deletion of GSK3β reduces atherosclerotic calcification [106], while phosphorylation of GSK3β could increase the stability of Snail and thus EndMT [77]. Tenascin-X inhibits EndMT by suppressing TGF-β signaling through its interaction with αvβ3 integrin, thereby preserving endothelial integrity and preventing the progression of atherosclerotic lesions [107].…”

GSK3 as a Master Regulator of Cellular Processes

“…Cai et al highlighted that vascular calcification in atherosclerotic lesions (a process involving endothelial-mesenchymal transition [16]) can be attenuated through pharmacological inhibition or the endothelial-specific deletion of GSK3β. In the murine apolipoprotein E (Apoe) knock-out (KO) atherosclerosis model, pharmacological GSK3 inhibition significantly reduced aortic calcification, calcium load, and the induction of osteogenic as well as mesenchymal markers in atherosclerotic lesions [17]. Equivalent results were obtained in mice, showing the endothelium-specific KO of GSK3β in response to tamoxifen [17], and have also been observed in diabetic Ins2 Akita/+ mice following GSK3β inhibition [18].…”

“…In the murine apolipoprotein E (Apoe) knock-out (KO) atherosclerosis model, pharmacological GSK3 inhibition significantly reduced aortic calcification, calcium load, and the induction of osteogenic as well as mesenchymal markers in atherosclerotic lesions [17]. Equivalent results were obtained in mice, showing the endothelium-specific KO of GSK3β in response to tamoxifen [17], and have also been observed in diabetic Ins2 Akita/+ mice following GSK3β inhibition [18]. In the study by Mastrogiacomo et al, the impact of GSK3α and β KOs in endothelial cells (EC) and/or macrophages for atherogenesis was assessed.…”