Simvastatin use associated with low intraocular ADP levels in patients with sight-threatening diabetic retinopathy

Abstract

Dear Editor, Purinergic signalling controls vascular thrombosis, remodelling and inflammation [1], and may result in disrupted blood flow and vascular function in the diabetic retina [2]. High glucose conditions increase secretion and reduce degradation of extracellular ATP in retinal cell culture [3], with increased purine concentrations being reported in the vitreous of diabetic patients suffering from proliferative retinopathy [4]. Administration of simvastatin, a lipophilic HMG-CoA reductase inhibitor, did not only promote direct vasculoprotective effects in experimental in vitro and ex vivo models [5], but was also associated with low levels of vasoactive and tissue remodelling factors in the retinas of diabetic rats [6] and vitreous of diabetic patients [7]. Here, we evaluated the vitreous accumulation of extracellular purine nucleotides in a total of 52 eyes of 52 type I and type II adult diabetic patients admitted to primary vitrectomy for the management of sight-threatening forms of diabetic retinopathy. The patients included those without statin medication (n = 41) and those with preoperative simvastatin treatment (n = 11). No difference emerged in the baseline characteristics of the patients (age, gender, HbA1c, body mass index, physical status, blood pressure, duration of diabetes) and vitrectomized eyes (intraocular pressure, lens status, intravitreal anti-VEGF treatment, macular oedema, proliferative retinopathy, vitreous haemorrhage, fibrosis) between the study groups. Vitreous samples were subjected to protein concentration measurements of adenosine 5’-triphosphate (ATP), -5’-diphosphate (ADP), -5’-monophosphate (AMP), adenosine and inosine. Intravitreal levels of proinflammatory and pro-thrombotic ADP were lower in simvastatin-treated diabetic patients (simvastatin vs. non-statin, mean ± SEM 42.9 ± 15.1 vs 7.7 ± 2.7 nM; p= 0.026, Table 1), while the data on other purinergic factors (ATP 34.5 ± 17.1 vs 6.1 ± 2.1; AMP 1974.3 ± 253.7 vs 1634.9 ± 253.4; adenosine 1066.3 ± 235.7 vs 1744.5 ± 419.5 and inosine 1163.0 ± 456.1 vs 2351.8 ± 1206.2, respectively, Table 1) led to a non-significant trend towards lower pro-inflammatory ATP and higher anti-inflammatory adenosine levels due to simvastatin treatment. These results suggest that simvastatin may favour dephosphorylation of extracellular ADP and shift the balance to an anti-inflammatory direction in the eye. Our findings are parallel with the previous report that statin use was associated with low plasma ADP levels in patients with atherosclerotic disease [8]. These data provide a novel insight into the potential vasculoprotective mechanisms of simvastatin involving extracellular purine nucleotides in patients with sight-threatening diabetic retinopathy. * Raimo Tuuminen raimo.tuuminen@helsinki.fi