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Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

ABSTRACT: Fabry disease is an X-linked lysosomal storage disease caused by mutations in the GLA gene that lead to a reduction or an absence of the enzyme ?-galactosidase A, resulting in the progressive and multisystemic accumulation of globotriaosylceramide. Clinical manifestation varies from mild to severe, depending on the phenotype. The main clinical manifestations are cutaneous (angiokeratomas), neurological (acroparesthesias), gastrointestinal (nausea, diarrhea abdominal pain), renal (proteinuria and kidney failure), cardiovascular (cardiomyopathy and arrhythmias), and cerebrovascular (stroke). A diagnosis of Fabry disease can be made with an enzymatic assay showing absent or reduced ?-galactosidase A in male patients, while in heterozygous female patients, molecular genetic testing is needed. Enzyme replacement therapy (ERT) with recombinant human ?-galactosidase is nowadays the most-used disease-specific therapeutic option. Despite ERT, cardiocerebrovascular-renal irreversible organ injury occurs, therefore additional knowledge and a deeper understanding of further pathophysiological mechanisms leading to end organ damage in Fabry disease are needed. Recent data point toward oxidative stress, oxidative stress signaling, and inflammation as some such mechanisms. In this short review, the current knowledge on the involvement of oxidative stress in cardiovascular-renal remodeling is summarized and related to the most recent evidence of oxidative stress activation in Fabry disease, and clearly points toward the involvement of oxidative stress in the pathophysiology of the medium- to long-term cardiovascular-renal damage of Fabry disease.

SUBMITTER: Ravarotto V

PROVIDER: S-EPMC6262438 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

Ravarotto Verdiana V Simioni Francesca F Carraro Gianni G Bertoldi Giovanni G Pagnin Elisa E Calò Lorenzo A LA

Journal of clinical medicine 20181102 11

Fabry disease is an X-linked lysosomal storage disease caused by mutations in the GLA gene that lead to a reduction or an absence of the enzyme α-galactosidase A, resulting in the progressive and multisystemic accumulation of globotriaosylceramide. Clinical manifestation varies from mild to severe, depending on the phenotype. The main clinical manifestations are cutaneous (angiokeratomas), neurological (acroparesthesias), gastrointestinal (nausea, diarrhea abdominal pain), renal (proteinuria and ...[more]

PMID: 30400144

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Project description:BackgroundFabry disease is characterized by deficient expression/activity of α-GalA with consequent lysosomal accumulation in various organs of its substrate Gb3. Despite enzyme replacement therapy, Fabry disease progresses with serious myocardial, cerebral and renal manifestations. Gb3 accumulation may induce oxidative stress (OxSt), production of inflammatory cytokines and reduction of nitric oxide, which may impact on Fabry disease's clinical manifestations.MethodsOxSt status was characterized in 10 patients compared with 10 healthy subjects via protein expression of p22phox, subunit of NADH/NADPH oxidase, (Western blot), Heme oxygenase (HO)-1 levels (ELISA), antioxidant/anti-inflammatory, lipid peroxidation as malondialdehyde (MDA) production (colorimetric assay), phosphorylation state of Extracellular Signal Regulated Kinase (ERK)1/2 and Myosin Phosphatase Target Protein (MYPT)-1 (Western blot), marker of Rho kinase activation, both involved in OxSt signaling. Cardiac left ventricular (LV) mass was also evaluated (M-mode echocardiography).ResultsLV mass was higher in Fabry's males (123.72±2.03SEM g/m2) and females (132.09±6.72g/m2). p22phox expression was also higher in patients (1.04±0.09 d.u. vs 0.54±0.05 d.u. p<0.01) as well as MDA levels (54.51±3.97 vs 30.05±7.11 nmol/mL p = 0.01) while HO-1 was reduced (8.84±0.79 vs 14.03±1.23 ng/mL, p<0.02). MYPT-1's phosphorylation was increased in patients (0.52±0.11 d.u. vs 0.03±0.08 d.u., p<0.01) while phosphorylation of ERK1/2 was reduced (0.91±0.08 d.u. vs 1.53±0.17 d.u., p = 0.004).ConclusionsThis study documents OxSt activation and the altered reaction to it in Fabry patients. Cardiac remodeling, Rho kinase signaling activation and reduction of protective HO-1 might suggest that, in addition to enzyme replacement therapy, OxSt inhibition by either pharmacological or nutritional measures, is likely to prove useful for the prevention/treatment of Fabry patients' cardiovascular-renal remodeling.

Project description:Leprosy reduces quality of life of affected persons. Oxidative stress caused by reactive oxygen species may play a vital role in the pathogenesis of leprosy. This study evaluated anthropometric indices, fasting plasma glucose (FPG), lipid profile, total antioxidant capacity (TAC), total plasma peroxide (TPP), oxidative stress index (OSI), malondialdehyde (MDA), glutathione (GSH) and 8-hydroxy-2-deoxyguanosine (8-OHdg) in leprosy patients. Sixty test participants of both genders, aged 18-65years and diagnosed of multibacillary leprosy and 30 apparently healthy controls were consecutively recruited for this study. The test participants comprised of 30 patients on multidrug therapy (MDT) and 30 patients relieved from therapy (RFT). Body mass index (BMI), Waist-hip ratio (WHR), FPG, lipid profile, TAC, TPP, OSI, MDA, GSH and 8-OHdg were determined using appropriate methods. Data were analyzed using Analysis of variance; p<0.05 was considered statistically significant. The MDT group had significantly lower BMI (p = 0.0001), Total cholesterol (p = 0.001), HDL-C (p = 0.019), LDL-C (p = 0.005), TAC (p = 0.0001) and higher TPP (p = 0.001), MDA (p = 0.0001), OSI (p = 0.005) and 8-OHdg (p = 0.035) compared to the controls. The RFT group had significantly lower BMI (p = 0.001) Total cholesterol (0.0001), HDL-C (p = 0.006) LDL-C (p = 0.0001), TAC (p = 0.001) and higher WHR (p = 0.010), VLDL-C (p = 0.035), TG (p = 0.023) Atherogenic index of plasma (p = 0.0001) and TPP (p = 0.001), MDA (p = 0.0001) compared to the control group. GSH levels correlated negatively with duration of treatment (r = -0.401, p = 0.028). This study has shown that there is oxidative stress in multibacillary leprosy patients irrespective of drug treatment status. This study also shows that leprosy patients relieved from treatment may be susceptible to cardiovascular events. Antioxidants supplementation may be beneficial in the treatment of leprosy and clinical follow up on patients relieved from treatment may also be necessary to monitor health status and prevent development of cardiovascular events.

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Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

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Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

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