Molecular mechanisms of statin effects in diabetic retinopathy

Hyperglycemia and increased generation of oxygen radicals stimulates vascular inflammation and this condition is cause of vascular injury and damage to the retina. The specific aims of this project are to define the molecular processes leading to diabetes induced vascular inflammation and to determine the potential benefits of the statin class of drugs (HMG-CoA reductase inhibitors) in preventing it. Statins are drugs normally used for lowering high cholesterol levels in patients at high risk of developing cardiovascular disease. However recent studies, aimed at monitoring the effectiveness of these drugs in log-term treatments, have been shown that statins possess remarkable vascular protective effects that are independent of their cholesterol-lowering actions. These protective effects have been observed in many cardiovascular diseases including diabetes, but very few studies have been conducted to specifically address their beneficial effects in diabetic retinopathy.

We will induce Type I diabetes in rats by injecting them with the antibiotic streptozotocin (STZ). STZ destroys the portion of the pancreas producing insulin (the Langherans islet) and the STZ-induced diabetic rat is a very established model of Type 1 diabetes. Signs of retinal vessels inflammation will be evaluated in the diabetic animals and compared to normal age-matched control rats and also to diabetic rats that have been treated with specific doses of the drug fluvastatin. This latter is a statin commonly used in clinical practice. As signs of inflammation, we will measure the activity and the formation of the pro-inflammatory factors VEGF, STAT3 and ICAM-1 and of the pro-oxidant factor Rac-1 and we will measure the amount of inflammatory cells adherent to the retinal microvessels. In addition, with a gene therapy based approach, we will block the activity of specific factors (STAT3 and Rac-1) involved in the production of oxygen radicals and of pro-inflammatory proteins in the diabetic rat retina.