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.
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.


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.
Zheng
Zhi
Z
Department of Ophthalmology, First People’s Hospital of Shanghai Affiliated to Shanghai Jiaotong University, Shanghai, China.
Chen
Haibing
H
Wang
Hong
H
Ke
Bilian
B
Zheng
Bingqing
B
Li
Qian
Q
Li
Peiyu
P
Su
Li
L
Gu
Qing
Q
Xu
Xun
X
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D002417:Cattle; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008564:Membrane Potentials / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000199:Actins; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047492:Peroxisome Proliferator-Activated Receptors; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D019821:Simvastatin