Parameters of oxidative stress are present in the circulation of PXE patients

Abstract

Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by calcification of elastic fibres leading to dermatological and vascular alterations associated to premature aged features and to life threatening clinical manifestations. The severity of the disease is independent from the type of mutation in the ABCC6 gene, and it has been suggested that local and/or systemic factors may contribute to the occurrence of clinical phenotype. The redox balance in the circulation of 27 PXE patients and of 50 healthy subjects of comparable age was evaluated by measuring the advanced oxidation protein products (AOPP), the lipid peroxidation derivatives (LOOH), the circulating total antioxidant status (TAS), the thiol content and the extracellular superoxide dismutase activity (EC-SOD). Patients were diagnosed by clinical, ultrastructural and molecular findings. Compared to control subjects, PXE patients exhibited significantly lower antioxidant potential, namely circulating TAS and free thiol groups, and higher levels of parameters of oxidative damage, as LOOH and of AOPP, and of circulating EC-SOD activity. Interestingly, the ratio between oxidant and antioxidant parameters was significantly altered in PXE patients and related to various score indices. This study demonstrates, for the first time, that several parameters of oxidative stress are modified in the blood of PXE patients and that the redox balance is significantly altered compared to control subjects of comparable age. Therefore, in PXE patients the circulating impaired redox balance may contribute to the occurrence of several clinical manifestations in PXE patients, and/or to the severity of disease, thus opening new perspectives for their management.

Is classical pseudoxanthoma elasticum a consequence of hepatic ‘intoxication’ due to ABCC6 substrate accumulation in the liver?

“…Moreover, oxidative imbalance has been documented Perspective in serum from PXE patients [64] and in liver and serum samples of the Abcc6 knockout mouse [65]. If oxidative stress potentiates PXE-derived mineralization, dietary antioxidant supplements may be of particular therapeutic interest as a means of counteracting mineral deposition.…”

The Multifaceted Complexity of Genetic Diseases: A Lesson from Pseudoxanthoma Elasticum

“…However, these data may indicate that i) other factors, beside ABCC6 expression are involved in the pathogenesis of calcifications, ii) responsive fibroblasts or other mesenchymal cells are required in order to modify connective tissue homeostasis, and iii) independently from the primary gene defect, common pathways may be involved in these disorders. Within this context, it has been suggested that the elastic tissue injury in these patients may be the result of an oxidative process, induced by the combined and interactive effects of different factors (Aessopos et al, 1998;Garcia-Fernandez et al, 2008;Pasquali-Ronchetti et al, 2006). Plasma membrane microparticles, derived from the oxidative damage of red cell membranes by the effect of denatured hemoglobin products and free iron (Olivieri, 1999), as well as unbound fractions of hemoglobin and haem, which exceed the binding capacity of haptoglobin and hemopexin in the context of chronic hemolysis, have been considered to elicit inflammatory and oxidative reactions (Belcher et al, 2000;Gutteridge & Smith, 1988).…”

“…Major advances concern diagnosis, due to ability to recognize a continuously increased number of mutations (mutation detection rate varies from 80-90%). Attempts to establish genotype/phenotype correlations have yielded little clinically useful information other than the fact that, as PXE patients age, symptoms get worse, probably because of progressive accumulation of mineralized elastic fibres, associated to other age-related degenerative features (Garcia-Fernandez et al, 2008). PXE is an important cause of blindness and of early death from cardiovascular manifestations (Neldner, 1988), therefore an early diagnosis is important in order to minimise the risk of systemic complications.…”

“…Actually, several studies have reported alterations in circulating factors in PXE patients, such as proteoglycans (Götting et al, 2005;Passi et al, 1996), plasma lipoproteins (Wang et al, 2001) and mineralization inhibitors, such as fetuin-A and Matrix Gla Protein (MGP) (Hendig et al, , 2008. Moreover, a number of circulating molecules have been shown to be modified in the plasma of PXE patients by effect of a systemic altered redox balance (Garcia-Fernandez et al, 2008). However, a number of questions remain to be elucidated.…”

“…However, in the light of these observations, changes in membrane transport properties described in PXE cultured fibroblasts (Boraldi et al, 2003) would seem likely the result of the high level of reactive oxygen species (ROS) on the structural organization of cell membranes (Boraldi et al, 2009) and consequently on cell permeability. It has been in fact demonstrated in vitro (Pasquali-Ronchetti et al, 2006) and in vivo (Garcia-Fernandez et al, 2008) that PXE is characterized by an altered redox balance. At cellular level, the chronic oxidative stress condition is due, at least in part, to the loss of mitochondrial membrane potential (ΔΨ (m)) with overproduction of ROS.…”