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Irisin promotes human umbilical vein endothelial cell proliferation through the ERK signaling pathway and partly suppresses high glucose-induced apoptosis.

Song H, Wu F, Zhang Y, Zhang Y, Wang F, Jiang M, Wang Z, Zhang M, Li S, Yang L, Wang XL, Cui T, Tang D - PLoS ONE (2014)

Bottom Line: Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs.It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression.In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Stem Cell & Regenerative Medicine, The Second Hospital of Shandong University, Jinan, P.R.China; Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, P.R.China; Center for Reproductive Medicine, Zibo Maternal and Child health hospital, Zibo, P.R.China.

ABSTRACT
Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal-related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.

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Irisin promoted HUVEC proliferation.(A) [3H] thymidine uptake in HUVECs that were cultured in M199 and treated with or without irisin at the indicated concentrations for 40 h. The data were expressed as the mean ± SE of three independent experiments,**p<0.01 vs. the untreated group. (B) Growth curves of HUVECs. HUVECs treated with or without irisin were constructed by plotting cell numbers that were counted using a hemocytometer over three days of incubation. ** p<0.01 vs. untreated, the data were expressed as the mean±SE of three independent experiments.
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pone-0110273-g001: Irisin promoted HUVEC proliferation.(A) [3H] thymidine uptake in HUVECs that were cultured in M199 and treated with or without irisin at the indicated concentrations for 40 h. The data were expressed as the mean ± SE of three independent experiments,**p<0.01 vs. the untreated group. (B) Growth curves of HUVECs. HUVECs treated with or without irisin were constructed by plotting cell numbers that were counted using a hemocytometer over three days of incubation. ** p<0.01 vs. untreated, the data were expressed as the mean±SE of three independent experiments.

Mentions: To investigate the role of irisin on HUVEC proliferation, [3H] thymidine uptake was measured as described in the materials and methods. It was observed that the increase of [3H] thymidine uptake induced by irisin (20 nM) was 2.4 times higher than the control group in serum-free conditions (Fig. 1A). To assess the actual cell number changes, the effects of irisin on HUVEC proliferation was detected by direct cell counting. The result demonstrated that irisin over a range of concentrations (20 and 40 nM) can significantly accelerate HUVEC proliferation (Fig. 1B). Considering that the maximum effect appeared when the irisin concentration was 20 nM, 20 nM Irisin was chosen for the following experiments. To further reveal the effect of irisin on HUVEC proliferation, anti-Ki67 immunofluorescent staining was used. Ki67 is a nuclear protein which is expressed in proliferating cells; thus, it may be essential for maintaining cell proliferation [11]. The results demonstrated that there were more Ki67-expressing cells in the irisin stimulation group than the control group (48.0±4.0% and 16.6±2.9%, respectively) (Fig. 2A), and the difference was statistically significant (P<0.01) (Fig. 2B).These data taken together suggested that irisin effectively promoted HUVEC proliferation in serum-free medium.


Irisin promotes human umbilical vein endothelial cell proliferation through the ERK signaling pathway and partly suppresses high glucose-induced apoptosis.

Song H, Wu F, Zhang Y, Zhang Y, Wang F, Jiang M, Wang Z, Zhang M, Li S, Yang L, Wang XL, Cui T, Tang D - PLoS ONE (2014)

Irisin promoted HUVEC proliferation.(A) [3H] thymidine uptake in HUVECs that were cultured in M199 and treated with or without irisin at the indicated concentrations for 40 h. The data were expressed as the mean ± SE of three independent experiments,**p<0.01 vs. the untreated group. (B) Growth curves of HUVECs. HUVECs treated with or without irisin were constructed by plotting cell numbers that were counted using a hemocytometer over three days of incubation. ** p<0.01 vs. untreated, the data were expressed as the mean±SE of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206299&req=5

pone-0110273-g001: Irisin promoted HUVEC proliferation.(A) [3H] thymidine uptake in HUVECs that were cultured in M199 and treated with or without irisin at the indicated concentrations for 40 h. The data were expressed as the mean ± SE of three independent experiments,**p<0.01 vs. the untreated group. (B) Growth curves of HUVECs. HUVECs treated with or without irisin were constructed by plotting cell numbers that were counted using a hemocytometer over three days of incubation. ** p<0.01 vs. untreated, the data were expressed as the mean±SE of three independent experiments.
Mentions: To investigate the role of irisin on HUVEC proliferation, [3H] thymidine uptake was measured as described in the materials and methods. It was observed that the increase of [3H] thymidine uptake induced by irisin (20 nM) was 2.4 times higher than the control group in serum-free conditions (Fig. 1A). To assess the actual cell number changes, the effects of irisin on HUVEC proliferation was detected by direct cell counting. The result demonstrated that irisin over a range of concentrations (20 and 40 nM) can significantly accelerate HUVEC proliferation (Fig. 1B). Considering that the maximum effect appeared when the irisin concentration was 20 nM, 20 nM Irisin was chosen for the following experiments. To further reveal the effect of irisin on HUVEC proliferation, anti-Ki67 immunofluorescent staining was used. Ki67 is a nuclear protein which is expressed in proliferating cells; thus, it may be essential for maintaining cell proliferation [11]. The results demonstrated that there were more Ki67-expressing cells in the irisin stimulation group than the control group (48.0±4.0% and 16.6±2.9%, respectively) (Fig. 2A), and the difference was statistically significant (P<0.01) (Fig. 2B).These data taken together suggested that irisin effectively promoted HUVEC proliferation in serum-free medium.

Bottom Line: Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs.It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression.In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Stem Cell & Regenerative Medicine, The Second Hospital of Shandong University, Jinan, P.R.China; Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, P.R.China; Center for Reproductive Medicine, Zibo Maternal and Child health hospital, Zibo, P.R.China.

ABSTRACT
Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal-related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.

Show MeSH
Related in: MedlinePlus