1. C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species--mediated transglutaminase 2 activation
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Bhatt, Mahendra Prasad, Lim, Young-Cheol, Hwang, JongYun, Na, SungHun, Kim, Young-Myeong, and Ha, Kwon-Soo
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Care and treatment ,Prevention ,Complications and side effects ,Genetic aspects ,Health aspects ,Apoptosis -- Prevention -- Genetic aspects ,Transglutaminases -- Health aspects ,Hyperglycemia -- Genetic aspects -- Complications and side effects -- Care and treatment ,Reactive oxygen species -- Health aspects - Abstract
Lack of C-peptide, along with insulin, is the main feature of type 1 diabetes mellitus (DM) and is also observed in progressive β-cell loss in later stage of type 2 [...], 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.sup.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.sup.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 + Coeptide, 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, Coeptide 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. Diabetes 62:243-253, 2013
- Published
- 2013
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