C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation.

Abstract

C-peptide is a bioactive peptide with a potentially protective role in diabetes complications; however, its molecular mechanism of protection against cardiovascular damage caused by hyperglycemia-induced apoptosis remains unclear. We investigated the protective mechanism of C-peptide against hyperglycemia-induced apoptosis using human umbilical vein endothelial cells and streptozotocin diabetic mice. High glucose (33 mmol/L) induced apoptotic cell death in endothelial cells via sequential elevation of intracellular Ca(2+) and reactive oxygen species (ROS) as well as subsequent activation of transglutaminase 2 (TG2). C-peptide (1 nmol/L) prevented endothelial cell death by inhibiting protein kinase C- and NADPH oxidase-dependent intracellular ROS generation and by abolishing high glucose-induced TG2 activation, without affecting intracellular Ca(2+) levels. Consistently, in the aorta of streptozotocin diabetic mice, hyperglycemia stimulated transamidating activity and endothelial cell apoptosis that was inhibited by C-peptide replacement therapy (35 pmol/min/kg) using osmotic pumps (control and diabetes, n = 8; diabetes + C-peptide, n = 7). In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice. Thus, C-peptide protects endothelial cells from hyperglycemia-induced apoptotic cell death by inhibiting intracellular ROS-mediated activation of TG2. Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies.

• Authors: Mahendra Prasad Bhatt, Young-Cheol Lim, JongYun Hwang, SungHun Na, Young-Myeong Kim, Kwon-Soo Ha
• Journal: Diabetes (Diabetes) Vol. 62 Issue 1 Pg. 243-53 (Jan 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 22923476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• C-Peptide
• Reactive Oxygen Species
• Streptozocin
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins
• Calcium

Topics

• Animals
• Apoptosis
• C-Peptide (physiology)
• Calcium (metabolism)
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism, pathology)
• Enzyme Activation
• GTP-Binding Proteins (antagonists & inhibitors, physiology)
• Human Umbilical Vein Endothelial Cells (pathology)
• Humans
• Hyperglycemia (pathology)
• Kidney Cortex (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (pathology)
• Protein Glutamine gamma Glutamyltransferase 2
• Reactive Oxygen Species (metabolism)
• Streptozocin
• Transglutaminases (antagonists & inhibitors, physiology)