Ginkgo Biloba Extract Reduces Endothelial Progenitor-Cell Senescence Through Augmentation of Telomerase Activity

Abstract

Our previous studies have shown that Ginkgo biloba extract increased endothelial progenitor-cell (EPC) numbers and functional activity. However, the mechanisms remain to be determined. Recent studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involved activation of telomerase. Therefore, we investigated whether Ginkgo biloba extract inhibited the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity. After ex vivo cultivation, EPCs became senescent as determined by acidic ss-galactosidase staining. Ginkgo biloba extract dose-dependently prevented the onset of EPC senescence in culture. Moreover, Ginkgo biloba extract increased proliferation of EPCs as assessed by MTT assay and colony-forming capacity. To get further insights into the underlying mechanisms of these effects, we measured telomerase activity and determined the phosphorylation of Akt by Western blotting. Ginkgo biloba extract significantly increased telomerase activity and phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, pretreatment with PI3K inhibitor, LY294002, significantly attenuated the Ginkgo biloba extract-induced telomerase activity. Taken together, the results indicated that Ginkgo biloba extract delayed the onset of EPC senescence, which may be related to activation of telomerase through the PI3k/Akt signaling pathway. The inhibition of EPC senescence by Ginkgo biloba extract in vitro may improve the functional activity of EPCs in a way that is important for potential cell therapy.

Aging Is Associated with a Proapoptotic Endothelial Progenitor Cell Phenotype

“…Thus, the greater apoptotic susceptibility in EPCs from older men may be due, at least in part, to overall lower expression of antiapoptotic proteins associated with the PI-3-kinase/Akt signaling pathway. In addition, telomerase activity has been shown to be inversely associated with intracellular caspase-3 activation [39]. Considering we observed approximately 60% less telomerase activity in EPCs from older men compared with younger men, it is possible that age-related reductions in telomerase activity may contribute to enhanced caspase-3 activation.…”

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

“…Telomerase activity may also impact apoptotic susceptibility. Dong et al (14) reported that elevated telomerase activity is associated with Akt phosphorylation, an upstream caspase-3 inhibitor, in endothelial progenitor cells treated with ginkgo biloba extract. Although we did not observe a significant relation between telomerase activity and caspase-3 activity in the present study, we cannot dismiss the possibility (due to our relatively modest sample size and the inherent interpretive causal limitations of correlation analysis) that reduced telomerase activity may contribute to the greater apoptotic susceptibility observed in the CD31 ϩ T cells from the middle-aged and older men.…”

Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide

“…As with ERK, AKT, in addition to the oxidant-inducing conditions cited above, has also been shown to be effective along with ERK in stress conditions involving glaucoma (Tatton et al 2003), telomerase activity (Dong et al 2007), acute LPS-induced inflammatory responses (Zhang et al 2007), endothelial cell protection by HDL (Norata and Catapano 2005), the rescue of AGE (2007) 29:191-203 neurons from MPTP-induced cell death (Weinreb et al 2006), N-methyl-D-aspartate receptors (NMDAR)-induced neuronal survival (Hetman and Kharebava 2006), and inhibition of glycogen synthase kinase-3 (GSK3) in the prevention of cell death in neurodegenerative diseases (Takashima 2006). The essential role of this enzyme for brain functions and behavior has been extensively studied (Blum et al 1999;Sweatt 2004;Webber et al 2005;Sahin et al 2006;Lee et al 2006).…”