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

OBJECTIVE—Mitochondrial reactive oxygen species (ROS) plays a key role in diabetic retinopathy (DR) pathogenesis. However, whether simvastatin decreases diabetes-induced mito-chondrial 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 coac-tivator 1 (PGC-1) 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 (m) and ROS production were assayed using the potentiometric dye 5,5,6,6- Tetrachloro1,1,3,3-tetraethyl-benzimidazolylcarbocya-nine iodide (JC-1) or CM-H2DCFDA fluorescent probes. RESULTS—Simvastatin significantly upregulated PGC-1 (P 0.01), subsequently decreased m (P 0.05) and ROS genera-tion (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 for-mation of acellular capillaries. CONCLUSIONS—Simvastatin decreases diabetes-induced mi-tochondrial 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-1. The understanding of the mechanisms of action of statins has important implications in the prevention and treat-ment of mitochondrial oxidative stress-related illness such a