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

Bhatt MP, Lim YC, Hwang J, Na S, Kim YM, Ha KS - Diabetes (2012)

Bottom Line: 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).In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice.Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea.

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.

Show MeSH

Related in: MedlinePlus

C-peptide inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis in heart and renal cortex. In vivo treatment of C-peptide (C-pep) using osmotic pumps inhibits transamidating activity and apoptosis stimulated by hyperglycemia in heart (A and B) and renal cortex (n = 8 for control and diabetes, n = 7 for diabetes + C-peptide) (C and D). Transamidating activity was determined by confocal microscopy (green) in heart (A) and renal cortex tissues (C). Arrows indicate myocardium and associated blood vessels (A) and renal cortex, including glomeruli (C). Apoptotic cells were stained with TUNEL (green, indicated by arrows) in heart (B) and renal cortex tissues (D). Nuclei were visualized with Hoechst dye 33258 (blue). Bar: 50 μm. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3526059&req=5

Figure 7: C-peptide inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis in heart and renal cortex. In vivo treatment of C-peptide (C-pep) using osmotic pumps inhibits transamidating activity and apoptosis stimulated by hyperglycemia in heart (A and B) and renal cortex (n = 8 for control and diabetes, n = 7 for diabetes + C-peptide) (C and D). Transamidating activity was determined by confocal microscopy (green) in heart (A) and renal cortex tissues (C). Arrows indicate myocardium and associated blood vessels (A) and renal cortex, including glomeruli (C). Apoptotic cells were stained with TUNEL (green, indicated by arrows) in heart (B) and renal cortex tissues (D). Nuclei were visualized with Hoechst dye 33258 (blue). Bar: 50 μm. (A high-quality color representation of this figure is available in the online issue.)

Mentions: Increased transamidating activity was observed in the myocardium and myocardial blood vessels (indicated by arrow) of diabetic mice compared with nondiabetic controls (Fig. 7A). However, C-peptide inhibited the activation of transamidating activity by hyperglycemia. TUNEL staining showed apoptotic cells in heart sections of diabetic mice, whereas apoptotic cells were rarely observed in heart tissue of nondiabetic control and C-peptide–supplemented diabetic mice (Fig. 7B). In addition, C-peptide prevented hyperglycemia-induced activation of transamidating activity and apoptosis in the renal cortex of diabetic mice (Fig. 7C and D). Our data suggest that C-peptide protects against hyperglycemia-induced apoptosis, probably by inhibiting TG2 transamidating activity in the aorta, heart, and kidney tissues of diabetic mice.


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

Bhatt MP, Lim YC, Hwang J, Na S, Kim YM, Ha KS - Diabetes (2012)

C-peptide inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis in heart and renal cortex. In vivo treatment of C-peptide (C-pep) using osmotic pumps inhibits transamidating activity and apoptosis stimulated by hyperglycemia in heart (A and B) and renal cortex (n = 8 for control and diabetes, n = 7 for diabetes + C-peptide) (C and D). Transamidating activity was determined by confocal microscopy (green) in heart (A) and renal cortex tissues (C). Arrows indicate myocardium and associated blood vessels (A) and renal cortex, including glomeruli (C). Apoptotic cells were stained with TUNEL (green, indicated by arrows) in heart (B) and renal cortex tissues (D). Nuclei were visualized with Hoechst dye 33258 (blue). Bar: 50 μm. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526059&req=5

Figure 7: C-peptide inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis in heart and renal cortex. In vivo treatment of C-peptide (C-pep) using osmotic pumps inhibits transamidating activity and apoptosis stimulated by hyperglycemia in heart (A and B) and renal cortex (n = 8 for control and diabetes, n = 7 for diabetes + C-peptide) (C and D). Transamidating activity was determined by confocal microscopy (green) in heart (A) and renal cortex tissues (C). Arrows indicate myocardium and associated blood vessels (A) and renal cortex, including glomeruli (C). Apoptotic cells were stained with TUNEL (green, indicated by arrows) in heart (B) and renal cortex tissues (D). Nuclei were visualized with Hoechst dye 33258 (blue). Bar: 50 μm. (A high-quality color representation of this figure is available in the online issue.)
Mentions: Increased transamidating activity was observed in the myocardium and myocardial blood vessels (indicated by arrow) of diabetic mice compared with nondiabetic controls (Fig. 7A). However, C-peptide inhibited the activation of transamidating activity by hyperglycemia. TUNEL staining showed apoptotic cells in heart sections of diabetic mice, whereas apoptotic cells were rarely observed in heart tissue of nondiabetic control and C-peptide–supplemented diabetic mice (Fig. 7B). In addition, C-peptide prevented hyperglycemia-induced activation of transamidating activity and apoptosis in the renal cortex of diabetic mice (Fig. 7C and D). Our data suggest that C-peptide protects against hyperglycemia-induced apoptosis, probably by inhibiting TG2 transamidating activity in the aorta, heart, and kidney tissues of diabetic mice.

Bottom Line: 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).In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice.Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea.

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.

Show MeSH
Related in: MedlinePlus