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HMG-CoA Reductase Inhibitors (Statin) Prevents Retinal Neovascularization in a Model of Oxygen-Induced Retinopathy

¹From the VA Medical Center, Augusta, Georgia; the ²Department of Ophthalmology, University of South Carolina School of Medicine, Columbia, South Carolina; ³Fondazione GB Bietti IRCCS, Onlus, Rome, Italy; the ⁴Departments of Oral Biology and Anatomy, School of Dentistry, ⁵Cellular Biology and Anatomy, Vascular Biology Center, and ⁷Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia; and the ⁶College of Pharmacy, University of Georgia, Augusta, Georgia.

PURPOSE. Retinal neovascularization (RNV) is a primary cause of blindness and involves the dysfunction of retinal capillaries. Recent studies have emphasized the beneficial effects of inhibitors of HMG-CoA reductase (statins) in preventing vascular dysfunction. In the present study, the authors characterized the therapeutic effects of statins on RNV.

METHODS. Statin treatment (10 mg/kg/d fluvastatin) was tested in a mouse model of oxygen-induced retinopathy. Morphometric analysis was conducted to determine the extent of capillary growth. Pimonidazole hydrochloride was used to assess retinal ischemia. Western blot and immunohistochemical analyses were used to assess protein expression levels and immunolocalization. Lipid peroxidation and superoxide radical formation were determined to assess oxidative changes.

RESULTS. Fluvastatin treatment significantly reduced the area of the capillary-free zone (P < 0.01), decreased the formation of neovascular tufts (P < 0.01), and ameliorated retinal ischemia. These morphologic and functional changes were associated with statin effects in preventing the upregulation of VEGF, HIF-1, phosphorylated STAT3, and vascular expression of the inflammatory mediator ICAM-1 (P < 0.01). Superoxide production and lipid peroxidation in the ischemic retina were also reduced by statin treatment (P < 0.01).

CONCLUSIONS. These data suggest the beneficial effects of statin treatment in preventing retinal neovascularization. These beneficial effects appear to result from the anti-oxidant and anti-inflammatory properties of statins.

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