CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

Abstract

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.

GSK3 inhibitor enhances gemtuzumab ozogamicin‐induced apoptosis in primary human leukemia cells by overcoming multiple mechanisms of resistance

“…Because GSK3α/β activity has been shown to affect lysosomal function [ 31 , 32 , 33 , 34 , 35 ], which is critical for scission of the link between GO and its toxic partner, calicheamicin, we asked whether activation of the PI3K/AKT/mTOR pathway would enhance the effects of GO by decreasing intra‐organellar pH. A positive effect was observed in all 6 cell lines.…”

“…On the other hand, the activity of mTORC1 is suppressed through Rheb suppression by the TSC1‐TSC2 complex [ 31 , 37 ]. Since TSC2 is also a target for GSK3, inhibition of GSK3 activity also causes mTORC1 inactivation [ 34 ]. In AML cell lines, CHIR99021 reduces phosphorylation of p70S6K, suggesting that mTORC1 is inactivated and lysosomal function is activated through the above pathways.…”

Assessing cardiovascular disease: looking beyond cholesterol

“…However, if the repair systems are impaired, or the damage is simply too extensive, plaque formation/growth will occur. This is probably why, as people become older, and the repair systems become less robust, a risk factor such as smoking becomes more significant [34].…”

Correction: Rethineswaran et al. CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence. Int. J. Mol. Sci. 2021, 22, 4796

“…There was an error in representative images of the tube formation in Figure 4 b in the original publication [ 1 ]. We inadvertently depicted the CHIR-treated image instead of CHIR+RAPA-treated groups in the representative image panel of Figure 4 b.…”