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High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.

Choi HY, Park JH, Jang WB, Ji ST, Jung SY, Kim da Y, Kang S, Kim YJ, Yun J, Kim JH, Baek SH, Kwon SM - Biomol Ther (Seoul) (2016)

Bottom Line: High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E.Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells.Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.

ABSTRACT
Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

No MeSH data available.


Related in: MedlinePlus

GLUT1 blocker rescues CPCs dysfunction in hyperglycemic conditions. (A) Percentage of viable hCPCs following treatment with Fasentin and 25 mM d-glucose for 72 h. hCPC viability was significantly increased with exposure to 1 μM Fasentin and 25 mM d-glucose for 72 h relative to that of the control. Results are presented as means ± SD. **p<0.01 vs. control. (B) Percentage of viable hCPCs following treatment with dapagliflozin and 25 mM d-glucose for 72 h. Viability was not significant different in hCPCs exposed to 1 μM dapagliflozin and 25 mM d-glucose for 72 h and in the control. Results are presented as means ± SD. *p<0.05 vs. control. **p<0.01 vs. control. (C) The tube formation ability of hCPCs treated with 1 μM Fasentin. Total tube length is presented in the lower panel. Results are presented as means ± SD. **p<0.01 vs. + 25 mM d-glucose.
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f5-bt-24-363: GLUT1 blocker rescues CPCs dysfunction in hyperglycemic conditions. (A) Percentage of viable hCPCs following treatment with Fasentin and 25 mM d-glucose for 72 h. hCPC viability was significantly increased with exposure to 1 μM Fasentin and 25 mM d-glucose for 72 h relative to that of the control. Results are presented as means ± SD. **p<0.01 vs. control. (B) Percentage of viable hCPCs following treatment with dapagliflozin and 25 mM d-glucose for 72 h. Viability was not significant different in hCPCs exposed to 1 μM dapagliflozin and 25 mM d-glucose for 72 h and in the control. Results are presented as means ± SD. *p<0.05 vs. control. **p<0.01 vs. control. (C) The tube formation ability of hCPCs treated with 1 μM Fasentin. Total tube length is presented in the lower panel. Results are presented as means ± SD. **p<0.01 vs. + 25 mM d-glucose.

Mentions: We next asked whether inhibition of d-glucose uptake by blocking the glucose transporter could rescue high-dose d-glucose-induced decreases in hCPC viability and cell cycling. We co-treated hCPCs with 25 mM d-glucose and 1 μM Fasentin or dapagliflozin, which block GLUT1 and SGLT2, respectively. Following co-treatment for 72 h, we performed WST and tube formation assays. First, we observed that co-treatment with 1 μM Fasentin and 25 mM d-glucose for 72 h significantly increased hCPC viability relative to that of the high-dose d-glucose treatment group (Fig. 5A). However, cells co-treated with 1 μM dapagliflozin and 25 mM d-glucose for 72 h did not differ from control cells (Fig. 5B). Thus, our data indicated that blocking glucose uptake through GLUT1-specific inhibition recovered hCPC viability that decreased with high doses of d-glucose. Amelioration of 25 mM d-glucose-induced dysfunction of hCPCs by co-treatment with 1 μM Fasentin was also associated with recovery of hCPC tube-forming ability (Fig. 5C). Therefore, the inhibition of glucose uptake by a specific inhibitor of GLUT1 improved the differentiation capacity of hCPCs.


High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.

Choi HY, Park JH, Jang WB, Ji ST, Jung SY, Kim da Y, Kang S, Kim YJ, Yun J, Kim JH, Baek SH, Kwon SM - Biomol Ther (Seoul) (2016)

GLUT1 blocker rescues CPCs dysfunction in hyperglycemic conditions. (A) Percentage of viable hCPCs following treatment with Fasentin and 25 mM d-glucose for 72 h. hCPC viability was significantly increased with exposure to 1 μM Fasentin and 25 mM d-glucose for 72 h relative to that of the control. Results are presented as means ± SD. **p<0.01 vs. control. (B) Percentage of viable hCPCs following treatment with dapagliflozin and 25 mM d-glucose for 72 h. Viability was not significant different in hCPCs exposed to 1 μM dapagliflozin and 25 mM d-glucose for 72 h and in the control. Results are presented as means ± SD. *p<0.05 vs. control. **p<0.01 vs. control. (C) The tube formation ability of hCPCs treated with 1 μM Fasentin. Total tube length is presented in the lower panel. Results are presented as means ± SD. **p<0.01 vs. + 25 mM d-glucose.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4930279&req=5

f5-bt-24-363: GLUT1 blocker rescues CPCs dysfunction in hyperglycemic conditions. (A) Percentage of viable hCPCs following treatment with Fasentin and 25 mM d-glucose for 72 h. hCPC viability was significantly increased with exposure to 1 μM Fasentin and 25 mM d-glucose for 72 h relative to that of the control. Results are presented as means ± SD. **p<0.01 vs. control. (B) Percentage of viable hCPCs following treatment with dapagliflozin and 25 mM d-glucose for 72 h. Viability was not significant different in hCPCs exposed to 1 μM dapagliflozin and 25 mM d-glucose for 72 h and in the control. Results are presented as means ± SD. *p<0.05 vs. control. **p<0.01 vs. control. (C) The tube formation ability of hCPCs treated with 1 μM Fasentin. Total tube length is presented in the lower panel. Results are presented as means ± SD. **p<0.01 vs. + 25 mM d-glucose.
Mentions: We next asked whether inhibition of d-glucose uptake by blocking the glucose transporter could rescue high-dose d-glucose-induced decreases in hCPC viability and cell cycling. We co-treated hCPCs with 25 mM d-glucose and 1 μM Fasentin or dapagliflozin, which block GLUT1 and SGLT2, respectively. Following co-treatment for 72 h, we performed WST and tube formation assays. First, we observed that co-treatment with 1 μM Fasentin and 25 mM d-glucose for 72 h significantly increased hCPC viability relative to that of the high-dose d-glucose treatment group (Fig. 5A). However, cells co-treated with 1 μM dapagliflozin and 25 mM d-glucose for 72 h did not differ from control cells (Fig. 5B). Thus, our data indicated that blocking glucose uptake through GLUT1-specific inhibition recovered hCPC viability that decreased with high doses of d-glucose. Amelioration of 25 mM d-glucose-induced dysfunction of hCPCs by co-treatment with 1 μM Fasentin was also associated with recovery of hCPC tube-forming ability (Fig. 5C). Therefore, the inhibition of glucose uptake by a specific inhibitor of GLUT1 improved the differentiation capacity of hCPCs.

Bottom Line: High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E.Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells.Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.

ABSTRACT
Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

No MeSH data available.


Related in: MedlinePlus