Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats.

Diabetic retinopathy (DR) is a multifactorial disease characterized by reactive gliosis and disbalance of angiogenesis regulators, contributing to endothelial dysfunction and microvascular complications. This study was organized to elucidate whether poly(ADP-ribose) polymerase-1 (PARP-1) inhibition could attenuate diabetes-induced damage to macroglia and correct angiogenic disbalance in diabetic rat retina. After 8 weeks of streptozotocin (STZ)-induced diabetes, Wistar male rats were treated with PARP-1 inhibitors, nicotinamide (NAm) or 3-aminobenzamide (3-AB) (100 and 30 mg/kg/daily i.p., respectively), for 14 days. After the 10-weeks experiment period, retinas were undergone an immunohistochemical staining for glial fibrillary acidic protein (GFAP), while western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of PARP-1, poly(ADP-ribosyl)ated proteins (PARs), GFAP, and angiostatin isoforms. Diabetes induced significant up-regulation and activation of retinal PARP-1, reactive gliosis development, and GFAP overexpression compared to non-diabetic control. Moreover, extensive fragmentation of both PARP-1 and GFAP (hallmarks of apoptosis and macroglia reactivation, respectively) in diabetic retina was also observed. Levels of angiostatin isoforms were dramatically decreased in diabetic retina, sustaining aberrant pro-angiogenic condition. Both NAm and 3-AB markedly attenuated damage to macroglia, evidenced by down-regulation of PARP-1, PARs and total GFAP compared to diabetic non-treated group. PARP-1-inhibitory therapy prevented formation of PARP-1 and GFAP cleavage-derived products. In retinas of anti-PARP-treated diabetic animals, partial restoration of angiostatin's levels was shown. Therefore, PARP-1 inhibitors counteract diabetes-induced injuries and manifest retinoprotective effects, including attenuation of reactive gliosis and improvement of angiogenic status, thus, such agents could be considered as promising candidates for DR management.

Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease.

AIM: Angiogenesis and chronic inflammation are known to be co-dependent in atherosclerosis and cardiovascular diseases. This study was undertaken to investigate whether simvastatin could affect serum levels of angiostatin, a potent endogenous inhibitor of neovascularization, in patients with ischemic heart disease (IHD). MAIN METHODS: Twenty-six patients with clinically confirmed IHD and hypercholesterolemia were assigned 40 mg/day of simvastatin for 8 weeks. Levels of lipid metabolism, C-reactive protein (C-RP) and other biochemical parameters in serum samples were measured using biochemical analyzer. Serum angiostatin levels were determined by Western blot. Association of serum angiostatin levels with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and C-RP levels was evaluated. KEY FINDINGS: Simvastatin therapy improved the main parameters of lipid metabolism, including statistically significant (P < 0.05) reductions in TC (by 46%) and LDL-C (by 42%), and decreased inflammatory marker C-RP (by 32%), as compared with the baseline. Simvastatin treatment resulted in marked reduction of serum angiostatin level (by 80% in comparison with baseline, P < 0.05). Strong positive correlations between serum angiostatin level versus concentrations of TC, LDL-C, and C-RP were demonstrated before onset of the study (r = 0.48311, 0.6252, and 0.653, respectively) and after simvastatin therapy (r = 0.67752, 0.6485, and 0.8244, respectively). SIGNIFICANCE: We describe for the first time novel pleiotropic effect of statin therapy associated with decrease of serum angiostatin levels. Thus, circulating angiostatin represents an independent additional risk marker for cardiovascular events and could be applied as potential supplementary indicator for evaluation of statin therapy efficacy.