Oxidative stress and the altered reaction to it in Fabry disease: A possible target for cardiovascular-renal remodeling?

Abstract

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.

The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

“…Cardiac energy metabolism was also shown to be altered in FD [ 35 ]. In GLA-null cardiomyocytes, Gb3 accumulation associates with impaired autophagic flux, alteration of mitochondrial membrane potential, and increased ROS production [ 40 , 63 , 64 ]. These evidence suggest the crosstalk between loss of GAL activity and mitochondria dysfunction in cardiac cells.…”

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

“…We have recently provided clear evidence, using a molecular biology approach, that in Fabry patients under ERT, oxidative stress is activated in terms of the increased protein expression of p22 phox and increased level of MDA, suggesting that in Fabry patients oxidative damage affects lipid structures—contributing in the medium- to long-term to the onset of pathological processes and leading to cardiovascular-renal and cerebrovascular damage [ 34 ]. Furthermore, we have shown that the Rho kinase pathway is activated in Fabry patients, evidencing a significantly increased phosphorylation status of its target MYPT-1 and suggesting that Rho kinase activation may play an important role in the oxidative stress signaling and cardiovascular renal remodeling of Fabry patients [ 34 ]. In addition, we have also shown an altered reaction to oxidative stress in Fabry patients in terms of the reduced production of Heme Oxigenase-1 [ 34 ], induced by and protective toward oxidative stress [ 35 ].…”

“…Furthermore, we have shown that the Rho kinase pathway is activated in Fabry patients, evidencing a significantly increased phosphorylation status of its target MYPT-1 and suggesting that Rho kinase activation may play an important role in the oxidative stress signaling and cardiovascular renal remodeling of Fabry patients [ 34 ]. In addition, we have also shown an altered reaction to oxidative stress in Fabry patients in terms of the reduced production of Heme Oxigenase-1 [ 34 ], induced by and protective toward oxidative stress [ 35 ]. This dysregulation—in addition to the Rho kinase signaling and oxidative stress activation—may further contribute to the cardiovascular-renal remodeling of Fabry patients, adding further information to our understanding of the pathophysiology of Fabry disease organ damage.…”

Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases

“…Gb-3 accumulation induced reactive oxygen species (ROS) production, suppressed mitochondrial antioxidant superoxide dismutase 2 (SOD2), and enhanced AMP-activated protein kinase (AMPK) activation in vascular endothelial cells and iPS cells derived from FD patients [72,73]. The cardiomyocytes (CM) differentiated from GLA-null embryonic stem cells (ESCs) showed accelerated level apoptosis due to impairment of protein degradation and autophagic flux in the presence of Gb-3 accumulation [74]. Also, MitoSOXRed staining demonstrated an increased level of residual oxygen consumption (ROX)production in GLA-null CMs [74].…”

“…The cardiomyocytes (CM) differentiated from GLA-null embryonic stem cells (ESCs) showed accelerated level apoptosis due to impairment of protein degradation and autophagic flux in the presence of Gb-3 accumulation [74]. Also, MitoSOXRed staining demonstrated an increased level of residual oxygen consumption (ROX)production in GLA-null CMs [74]. Therefore, dysfunctional mitochondria could be a source of ROS elevation.…”