C-Peptide Prevents Hyperglycemia-Induced Endothelial Apoptosis Through Inhibition of Reactive Oxygen Species―Mediated Transglutaminase 2 Activation

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 1; pp. 243 - 253
• Main Authors: MAHENDRA PRASAD BHATT, LIM, Young-Cheol, HWANG, Jongyun, NA, Sunghun, KIM, Young-Myeong, HA, Kwon-Soo
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2013
• Subjects: Animals; Apoptosis; Biological and medical sciences; C-Peptide - physiology; Calcium - metabolism; Care and treatment; Cell death; Cells, Cultured; Complications; Complications and side effects; Coronary vessels; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Diabetic neuropathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Glucose; Growth factors; GTP-Binding Proteins - antagonists & inhibitors; GTP-Binding Proteins - physiology; Health aspects; Human Umbilical Vein Endothelial Cells - pathology; Humans; Hyperglycemia; Hyperglycemia - pathology; Investigations; Kidney Cortex - pathology; Kinases; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microscopy; Myocardium - pathology; Peptides; Phenols; Prevention; Reactive oxygen species; Reactive Oxygen Species - metabolism; Streptozocin; Transglutaminases; Transglutaminases - antagonists & inhibitors; Transglutaminases - physiology; Veins & arteries; South Korea; Endocrinopathy; Acyltransferases; Reactive oxygen species; Enzyme; Transferases; Diabetes mellitus; Aminoacyltransferases; C-Peptide; Endothelium; Hyperglycemia; Cell death; Blood vessel; Circulatory system; Inhibition; Protein-glutamine γ-glutamyltransferase; Apoptosis
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db12-0293

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.