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

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.

Cytoprotective Roles of a Novel Compound, MHY‐1684, against Hyperglycemia‐Induced Oxidative Stress and Mitochondrial Dysfunction in Human Cardiac Progenitor Cells

“…Based on a previous report that hyperglycemia-induced apoptosis is caused by mitochondrial ROS [ 17 ], we investigated the effect of MHY-1684 on hyperglycemia-induced mitochondrial ROS generation. As shown in Figure 3(a) , when exposed to hyperglycemia, hCPCs produced more mitochondrial ROS.…”

“…Maintaining mitochondrial dynamics is an important part of tissue homeostasis in that disordered mitochondrial dynamics is associated with various diseases [ 27 ]. Existing evidence also suggests that mitochondrial fragmentation occurs during hyperglycemia and thereby causes hCPC dysfunction [ 17 ]. Our results support the importance of the proper modulation of hyperglycemia-related mitochondrial dynamics.…”

“…Accumulating evidence has suggested that mitochondrial dynamics including mitochondrial fission and fusion maintain mitochondrial homeostasis [ 16 ]. For example, several research groups have clearly demonstrated the specific disruption of mitochondrial dynamics by fission-related inhibitors including specific targeting of dynamin-related protein 1 (Drp-1), which eventually induces cell death and promotes heart disease [ 17 – 19 ]. Multiple therapeutic strategies have been attempted, including the specific targeting of ROS-induced mitochondrial fragmentation [ 20 ], hyperglycemia-related cardiac stem cell homing [ 21 ], and hyperglycemia-induced angiogenic capacity of CPCs [ 9 ].…”

“…Recently, we also reported that hyperglycemia in CPCs alters mitochondrial dynamics and increases the expression of fission-related proteins, including mitochondrial fission 1 protein (Fis1) and Drp1. Moreover, we showed that the specific blockage of glucose transporter 1 (GLUT1) improved cell viability, tube formation, and regulation of mitochondrial dynamics in CPCs [ 17 ]. Nevertheless, there are still few reports that identify novel compounds for enhancing CPC bioactivities against DCM.…”

Eat, breathe, ROS: controlling stem cell fate through metabolism

“…CPC migration is also improved by hypoxia, suggesting enhanced mobilization [93]. However, excessive glucose may also be detrimental to CPCs, as culture of human c-Kit + CPCs in supra-physiological glucose conditions (up to 25 mM) results in mitochondrial fragmentation, impaired endothelial-lineage differentiation, and cell death [94]. Importance of ROS in CPC differentiation is demonstrated by inhibition of Nox2 or Nox4 in freshly isolated CPCs suppressing cardiac and smooth muscle lineage commitment while maintaining stem cell marker expression [95].…”