Dipeptidyl peptidase-4 inhibitor sitagliptin prevents high glucose-induced apoptosis via activation of AMP-activated protein kinase in endothelial cells

Resveratrol (RSV) is used as a protective therapy against diabetic retinopathy. However, the mechanism(s) underlying this protective effect has not been fully elucidated. Bovine retinal capillary endothelial cells (BRECs), an in vitro model, were used to investigate the mechanism of RSV. Our results showed that high glucose induced significant cellular apoptosis in BRECs, which was accompanied by increased intracellular levels of reactive oxygen species (ROS) and cleaved caspase-3. The glucose-induced apoptosis and ROS elevation were both inhibited by RSV. High glucose was found to decrease the levels of phosphorylated AMP-activated protein kinase (p-AMPK), which was accompanied by increased levels of Sirt1 and PGC-1α. These changes were reversed by RSV. We also demonstrated that AMPK regulates the modulations of Sirt1 and PGC-1α using specific inhibitors of AMPK and Sirt1 and small interfering RNAs of PGC-1α. In summary, the current study demonstrates that RSV is effective against high glucose-induced cellular apoptosis and its action is exerted via the inhibition of ROS/AMPK/Sirt1/PGC-1α pathway.

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GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells

Molecular Biology Reports ◽

10.1007/s11033-012-2290-8 ◽

2012 ◽

Vol 40 (3) ◽

pp. 2273-2279 ◽

Cited By ~ 9

Author(s):

Hu Y ◽

Liu HB ◽

Simpson RW ◽

Dear AE

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Dipeptidyl Peptidase ◽

Vascular Endothelial ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitor ◽

Independent Effects

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Carbon monoxide (from CORM-2) inhibits high glucose-induced ICAM-1 expression via AMP-activated protein kinase and PPAR-γ activations in endothelial cells

Atherosclerosis ◽

10.1016/j.atherosclerosis.2009.05.008 ◽

2009 ◽

Vol 207 (2) ◽

pp. 405-411 ◽

Cited By ~ 24

Author(s):

Irina Tsoy Nizamutdinova ◽

Young Min Kim ◽

Hye Jung Kim ◽

Han Geuk Seo ◽

Jae Heun Lee ◽

...

Keyword(s):

Carbon Monoxide ◽

Endothelial Cells ◽

Protein Kinase ◽

High Glucose ◽

Ppar Γ ◽

Amp Activated Protein Kinase

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Adiponectin inhibits palmitate-induced apoptosis through suppression of reactive oxygen species in endothelial cells: involvement of cAMP/protein kinase A and AMP-activated protein kinase

Journal of Endocrinology ◽

10.1677/joe-10-0093 ◽

2010 ◽

Vol 207 (1) ◽

pp. 35-44 ◽

Cited By ~ 63

Author(s):

Ji-Eun Kim ◽

Seung Eun Song ◽

Yong-Woon Kim ◽

Jong-Yeon Kim ◽

Sung-Chul Park ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Cells ◽

Protein Kinase ◽

Inhibitory Effect ◽

Ros Generation ◽

Oxygen Species ◽

Compound C ◽

Induced Apoptosis ◽

Amp Activated Protein Kinase ◽

Kinase A

The present study examined whether adiponectin can inhibit palmitate-induced apoptosis, and also the associated mechanisms and signal transduction pathways in human umbilical vein endothelial cells. Cells treated with 500 μM palmitate for 48 h increased reactive oxygen species (ROS) generation and induced apoptosis. Treatment with antioxidant N-acetyl-l-cysteine (1 mM) and globular adiponectin (5 μg/ml) inhibited palmitate-induced ROS generation and apoptosis. The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 1 mM), and cAMP activators forskolin (10 μM) and cholera toxin (200 ng/ml) also displayed the same effects. The inhibitory effects of adiponectin on ROS generation and apoptosis were reversed by the AMPK inhibitor compound C (40 μM), cAMP inhibitor SQ22536 (50 μM), and protein kinase A (PKA) inhibitor H-89 (10 μM). The inhibitory effect of forskolin on palmitate-induced apoptosis was reversed by compound C, whereas the inhibitory effect of AICAR was not reversed by SQ22536 and H-89. AICAR and forskolin could not inhibit palmitate-induced apoptosis in cells treated with dominant-negative AMPK. Forskolin increased phosphorylated AMPK at both Thr-172 and Ser-485/491. These results suggest that adiponectin inhibits palmitate-induced apoptosis by suppression of ROS generation via both the cAMP/PKA and AMPK pathways. Interaction between cAMP/PKA and AMPK pathways may be involved.

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