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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

Proteins related to mitochondrial dynamics in hCPC culture medium containing high doses of d-glucose. (A) Western blot analysis of fission-related proteins (Fis1 and Drp1) in high dose-exposed hCPCs and control. hCPCs treated with high doses of d-glucose showed significantly higher Fis1 and Drp1 expression than untreated hCPCs. (B) Western blot analysis of fusion-related proteins (Mfn1, Mfn2, and OPA1) in high dose-exposed hCPCs and control. Treatment with high doses of d-glucose showed no effects on Mfn1, Mfn2, and OPA1 expression in hCPCs.
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f4-bt-24-363: Proteins related to mitochondrial dynamics in hCPC culture medium containing high doses of d-glucose. (A) Western blot analysis of fission-related proteins (Fis1 and Drp1) in high dose-exposed hCPCs and control. hCPCs treated with high doses of d-glucose showed significantly higher Fis1 and Drp1 expression than untreated hCPCs. (B) Western blot analysis of fusion-related proteins (Mfn1, Mfn2, and OPA1) in high dose-exposed hCPCs and control. Treatment with high doses of d-glucose showed no effects on Mfn1, Mfn2, and OPA1 expression in hCPCs.

Mentions: To examine which molecules, those associated with mitochondrial fusion or mitochondrial fission, mediated mitochondrial fragmentation in a high d-glucose environment, we treated hCPCs with a high dose of d-glucose for 24 h and 72 h and performed a western blot analysis. While no significant difference in the levels of mitochondrial fusion-related proteins Mfn1, Mfn2, and OPA1 was detected between d-glucose- and vehicle-treated hCPCs (Fig. 4B), the mitochondrial fission-related proteins Drp1 and Fis1 were greatly increased in the high-dose d-glucose treatment groups (Fig. 4A). These results indicate that the molecules that regulate mitochondrial fission increase with high doses of d-glucose, contributing to an imbalance in mitochondrial dynamics that favors fission.


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)

Proteins related to mitochondrial dynamics in hCPC culture medium containing high doses of d-glucose. (A) Western blot analysis of fission-related proteins (Fis1 and Drp1) in high dose-exposed hCPCs and control. hCPCs treated with high doses of d-glucose showed significantly higher Fis1 and Drp1 expression than untreated hCPCs. (B) Western blot analysis of fusion-related proteins (Mfn1, Mfn2, and OPA1) in high dose-exposed hCPCs and control. Treatment with high doses of d-glucose showed no effects on Mfn1, Mfn2, and OPA1 expression in hCPCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-bt-24-363: Proteins related to mitochondrial dynamics in hCPC culture medium containing high doses of d-glucose. (A) Western blot analysis of fission-related proteins (Fis1 and Drp1) in high dose-exposed hCPCs and control. hCPCs treated with high doses of d-glucose showed significantly higher Fis1 and Drp1 expression than untreated hCPCs. (B) Western blot analysis of fusion-related proteins (Mfn1, Mfn2, and OPA1) in high dose-exposed hCPCs and control. Treatment with high doses of d-glucose showed no effects on Mfn1, Mfn2, and OPA1 expression in hCPCs.
Mentions: To examine which molecules, those associated with mitochondrial fusion or mitochondrial fission, mediated mitochondrial fragmentation in a high d-glucose environment, we treated hCPCs with a high dose of d-glucose for 24 h and 72 h and performed a western blot analysis. While no significant difference in the levels of mitochondrial fusion-related proteins Mfn1, Mfn2, and OPA1 was detected between d-glucose- and vehicle-treated hCPCs (Fig. 4B), the mitochondrial fission-related proteins Drp1 and Fis1 were greatly increased in the high-dose d-glucose treatment groups (Fig. 4A). These results indicate that the molecules that regulate mitochondrial fission increase with high doses of d-glucose, contributing to an imbalance in mitochondrial dynamics that favors fission.

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