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Improvement of retinal vascular injury in diabetic rats by statins is associated with the inhibition of mitochondrial reactive oxygen species pathway mediated by peroxisome proliferator-activated receptor gamma coactivator 1alpha.

Zheng Z, Chen H, Wang H, Ke B, Zheng B, Li Q, Li P, Su L, Gu Q, Xu X - Diabetes (2010)

Bottom Line: The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage.Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01).Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, First People’s Hospital of Shanghai Affiliated to Shanghai Jiaotong University, Shanghai, China.

ABSTRACT

Objective: Mitochondrial reactive oxygen species (ROS) plays a key role in diabetic retinopathy (DR) pathogenesis. However, whether simvastatin decreases diabetes-induced mitochondrial ROS production remains uncertain. The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage.

Research design and methods: Diabetic rats and control animals were randomly assigned to receive simvastatin or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without simvastatin. Vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in the rat retinas or BRECs were examined by Western blotting and real-time RT-PCR, and poly (ADP-ribose) polymerase (PARP), and p38 MAPK were examined by Western blotting. Mitochondrial membrane potential (Deltapsim) and ROS production were assayed using the potentiometric dye 5,5',6,6'- Tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1) or CM-H(2)DCFDA fluorescent probes.

Results: Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01). Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries.

Conclusions: Simvastatin decreases diabetes-induced mitochondrial ROS production and exerts protective effects against early retinal vascular damage in diabetic rats in association with the inhibition of mitochondrial ROS/PARP pathway mediated by PGC-1alpha. The understanding of the mechanisms of action of statins has important implications in the prevention and treatment of mitochondrial oxidative stress-related illness such as DR.

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Changes of retinal VEGF levels in the control rats (control), diabetic rats (DM), and diabetic rats treated with simvastatin (DM + S). A: Real-time RT-PCR determination of VEGF mRNAs relative to the control values. B: Western blot analysis of VEGF protein expression in the three groups. Equal protein loading was confirmed by detection of β-actin. C: Retinal vascular permeability in the three groups. Bars indicate SD. A representative experiment of the three is shown (**P < 0.01 vs. control; ##P < 0.01 vs. DM; n = 8).
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Figure 1: Changes of retinal VEGF levels in the control rats (control), diabetic rats (DM), and diabetic rats treated with simvastatin (DM + S). A: Real-time RT-PCR determination of VEGF mRNAs relative to the control values. B: Western blot analysis of VEGF protein expression in the three groups. Equal protein loading was confirmed by detection of β-actin. C: Retinal vascular permeability in the three groups. Bars indicate SD. A representative experiment of the three is shown (**P < 0.01 vs. control; ##P < 0.01 vs. DM; n = 8).

Mentions: Compared with the control, the VEGF mRNA and protein were upregulated significantly in the retinas of diabetic rats with a concomitant increase in retinal vascular permeability, whereas simvastatin significantly inhibited these changes (Fig. 1A–C). Pearson correlation tests showed significant positive correlations between the changes in retinal vascular permeability and the changes in VEGF expression in diabetic rats with or without treatment with simvastatin (data not shown).


Improvement of retinal vascular injury in diabetic rats by statins is associated with the inhibition of mitochondrial reactive oxygen species pathway mediated by peroxisome proliferator-activated receptor gamma coactivator 1alpha.

Zheng Z, Chen H, Wang H, Ke B, Zheng B, Li Q, Li P, Su L, Gu Q, Xu X - Diabetes (2010)

Changes of retinal VEGF levels in the control rats (control), diabetic rats (DM), and diabetic rats treated with simvastatin (DM + S). A: Real-time RT-PCR determination of VEGF mRNAs relative to the control values. B: Western blot analysis of VEGF protein expression in the three groups. Equal protein loading was confirmed by detection of β-actin. C: Retinal vascular permeability in the three groups. Bars indicate SD. A representative experiment of the three is shown (**P < 0.01 vs. control; ##P < 0.01 vs. DM; n = 8).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927955&req=5

Figure 1: Changes of retinal VEGF levels in the control rats (control), diabetic rats (DM), and diabetic rats treated with simvastatin (DM + S). A: Real-time RT-PCR determination of VEGF mRNAs relative to the control values. B: Western blot analysis of VEGF protein expression in the three groups. Equal protein loading was confirmed by detection of β-actin. C: Retinal vascular permeability in the three groups. Bars indicate SD. A representative experiment of the three is shown (**P < 0.01 vs. control; ##P < 0.01 vs. DM; n = 8).
Mentions: Compared with the control, the VEGF mRNA and protein were upregulated significantly in the retinas of diabetic rats with a concomitant increase in retinal vascular permeability, whereas simvastatin significantly inhibited these changes (Fig. 1A–C). Pearson correlation tests showed significant positive correlations between the changes in retinal vascular permeability and the changes in VEGF expression in diabetic rats with or without treatment with simvastatin (data not shown).

Bottom Line: The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage.Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01).Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, First People’s Hospital of Shanghai Affiliated to Shanghai Jiaotong University, Shanghai, China.

ABSTRACT

Objective: Mitochondrial reactive oxygen species (ROS) plays a key role in diabetic retinopathy (DR) pathogenesis. However, whether simvastatin decreases diabetes-induced mitochondrial ROS production remains uncertain. The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage.

Research design and methods: Diabetic rats and control animals were randomly assigned to receive simvastatin or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without simvastatin. Vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in the rat retinas or BRECs were examined by Western blotting and real-time RT-PCR, and poly (ADP-ribose) polymerase (PARP), and p38 MAPK were examined by Western blotting. Mitochondrial membrane potential (Deltapsim) and ROS production were assayed using the potentiometric dye 5,5',6,6'- Tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1) or CM-H(2)DCFDA fluorescent probes.

Results: Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01). Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries.

Conclusions: Simvastatin decreases diabetes-induced mitochondrial ROS production and exerts protective effects against early retinal vascular damage in diabetic rats in association with the inhibition of mitochondrial ROS/PARP pathway mediated by PGC-1alpha. The understanding of the mechanisms of action of statins has important implications in the prevention and treatment of mitochondrial oxidative stress-related illness such as DR.

Show MeSH
Related in: MedlinePlus