MO024: Effect of green tea on top of enzyme replacement therapy in patients with Fabry disease: a molecular biology approach

Abstract

Abstract BACKGROUND AND AIMS Fabry disease (FD) is an X-linked rare disease characterized by deficient expression and activity of alpha-galactosidase A and consequent lysosomal accumulation of Gb3 and derivatives in various organs. Notwithstanding the first-line treatment with enzyme replacement therapy (ERT), FD progresses with serious cardiovascular, renal and cerebral implications in particular in case of late diagnosis. This suggests the involvement of secondary parallel mechanisms to Gb3 accumulation. We have shown that FD patients have increased and active oxidative stress (OxSt), which plays a primary role in the induction of cardiovascular–renal remodeling and contributes in these patients to the associated left ventricular hypertrophy (LVH). We have also shown that in dialysis and CKD stage 3–4 patients, another population with high cardiovascular risk, antioxidant treatment with green tea significantly reduced OxSt-related cell signaling mechanisms improving LVH. We have therefore hypothesized that inpatients with FD, green tea on top of ERT might have additive positive effects toward OxSt and OxSt-induced cardiovascular–renal remodeling using a molecular biologic approach. METHOD Ten naïve Fabry patients were enrolled and evaluated ex vivo in mononuclear cells the status of OxSt before ERT, after 12 months of ERT and after 6 months of the additional treatment with two capsules of green tea (600 mg Camellia Sinensis leaves dry extract, 40% Epigallocathechinegallate, Frama S.r.l., Noventa Padovana, Italy) per day taken in the morning at fast on top of ERT. The OxSt was evaluated and compared in the tree time periods in terms of protein expression of p22phox (subunit of NADH/NADPH oxidase essential for the production of superoxide), phosphorylation state of MYPT-1 (regulatory subunit of the myosin light chain phosphatase), ERK 1/2 (effectors at nuclear level of cardiovascular remodeling) and plasma levels of MDA (marker of lipid peroxidation). HO-1 levels (antioxidant and protective from OxSt) were also evaluated. RESULTS p22phox was significantly decreased after 12 months of enzymatic therapy and further decreased after 6 months of green tea treatment (1.91 ± 0.83 versus 1.10 ± 0.23 versus 0.83 ± 0.20 d.u.), same for MYPT-1 phosphorylation (0.81 ± 0.20 versus 0.68 ± 0.21 versus 0.52 ± 0.11 d.u.). The phosphorylation of ERK 1/2 remained unchanged after 12 months of ERT, but significantly decreased after 6 months of green tea supplementation (1.06 ± 0.24 versus 1.02 ± 0.27 versus 0.76 ± 0.14 d.u.) as well as MDA levels (5.50 ± 1.08 versus 5.10 ± 1.1 versus 4.16 ± 0.86 nmol/mL). Finally, HO-1 significantly increased with both ERT and green tea supplementation (1.37 ± 0.34 versus 1.67 ± 0.51 versus 1.96 ± 0.53 ng/mL). CONCLUSION This study provides data pointing toward an antioxidant effect exerted by ERT itself, which is further amplified by the treatment with green tea on top of ERT. These data while on one hand highlight the fundamental importance of an early diagnosis and treatment of FD, on the other hand suggest the need of adjuvant antioxidant treatments to prevent or improve specific disease manifestations.