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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

High doses of d-glucose alter the morphologies of mitochondria in hCPCs. (A, C) Images of hCPCs stained with MitoTracker Red CMXRos after of 24 h (A) and 72 h (C) of incubation in medium containing 5 mM, 15 mM, or 25 mM d-glucose. The arrows indicate tubular mitochondria in hCPCs treated with high doses of d-glucose. (B, D) Mitochondrial length in hCPCs incubated in media with high doses of d-glucose for 24 h (B) or 72 h (D). Results are presented as means ± SD. **p<0.01 vs. control.
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f3-bt-24-363: High doses of d-glucose alter the morphologies of mitochondria in hCPCs. (A, C) Images of hCPCs stained with MitoTracker Red CMXRos after of 24 h (A) and 72 h (C) of incubation in medium containing 5 mM, 15 mM, or 25 mM d-glucose. The arrows indicate tubular mitochondria in hCPCs treated with high doses of d-glucose. (B, D) Mitochondrial length in hCPCs incubated in media with high doses of d-glucose for 24 h (B) or 72 h (D). Results are presented as means ± SD. **p<0.01 vs. control.

Mentions: Alterations in the extracellular environment, including the initiation of hyperglycemia, hyperinsulinemia, or hyperlipidemia, cause mitochondrial dysfunction in T2DM (Guilherme et al., 2008; Muoio and Newgard, 2008). To investigate whether hyperglycemia is involved in modifying mitochondrial dynamics, we treated hCPCs with a high dose of d-glucose for 24 h and 72 h, and used MitoTracker Red CMXRos to stain mitochondria and obtained images under an fluorescence microscope. Mitochondria appeared as fragmented, discontinuous networks after hCPCs were treated with 25 mM d-glucose for 24 h or with 15 mM or 25 mM d-glucose for 72 h (Fig. 3A, 3C). Determination of the total lengths of mitochondria revealed that treatment with high doses of d-glucose shifted mitochondrial morphology toward a fission type in a time- and dose-dependent manner (Fig. 3B, 3D).


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)

High doses of d-glucose alter the morphologies of mitochondria in hCPCs. (A, C) Images of hCPCs stained with MitoTracker Red CMXRos after of 24 h (A) and 72 h (C) of incubation in medium containing 5 mM, 15 mM, or 25 mM d-glucose. The arrows indicate tubular mitochondria in hCPCs treated with high doses of d-glucose. (B, D) Mitochondrial length in hCPCs incubated in media with high doses of d-glucose for 24 h (B) or 72 h (D). Results are presented as means ± SD. **p<0.01 vs. control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-bt-24-363: High doses of d-glucose alter the morphologies of mitochondria in hCPCs. (A, C) Images of hCPCs stained with MitoTracker Red CMXRos after of 24 h (A) and 72 h (C) of incubation in medium containing 5 mM, 15 mM, or 25 mM d-glucose. The arrows indicate tubular mitochondria in hCPCs treated with high doses of d-glucose. (B, D) Mitochondrial length in hCPCs incubated in media with high doses of d-glucose for 24 h (B) or 72 h (D). Results are presented as means ± SD. **p<0.01 vs. control.
Mentions: Alterations in the extracellular environment, including the initiation of hyperglycemia, hyperinsulinemia, or hyperlipidemia, cause mitochondrial dysfunction in T2DM (Guilherme et al., 2008; Muoio and Newgard, 2008). To investigate whether hyperglycemia is involved in modifying mitochondrial dynamics, we treated hCPCs with a high dose of d-glucose for 24 h and 72 h, and used MitoTracker Red CMXRos to stain mitochondria and obtained images under an fluorescence microscope. Mitochondria appeared as fragmented, discontinuous networks after hCPCs were treated with 25 mM d-glucose for 24 h or with 15 mM or 25 mM d-glucose for 72 h (Fig. 3A, 3C). Determination of the total lengths of mitochondria revealed that treatment with high doses of d-glucose shifted mitochondrial morphology toward a fission type in a time- and dose-dependent manner (Fig. 3B, 3D).

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