Antioxidants May Help Prevent Damage to Heart, Kidneys in Fabry Patients, Research Suggests
Inhibition of oxidative compounds using pharmacological or nutritional approaches, in addition to enzyme replacement therapy, may benefit patients with Fabry disease, research suggests.
Treatment with antioxidant agents may help prevent the progressive damage in the heart and kidneys experienced by these patients.
Fabry disease is characterized by the progressive tissue accumulation of globotriaosylceramide (Gb3), and other fatty molecules due to a faulty α-GalA enzyme. The disease’s most severe manifestations affect mainly the blood vessels, leading to cerebrovascular disease, cardiac disease, and progressive renal failure.
With the development of enzyme replacement therapies, such as Shire’s Replagal (agalsidase-alfa) and Sanofi Genzyme’s Fabrazyme (agalsidase-beta), it became possible to effectively prevent Gb3 accumulation and even reduce its levels.
However, these therapies are unable to change the natural course of Fabry-associated cardiac, cerebrovascular, or renal disease, especially in more advanced cases, suggesting that the development of these secondary disorders is not solely caused by Gb3 buildup, but also other cellular events.
Oxidative stress is central in cardiovascular-renal remodeling that represents the most common cause of excess morbidity and mortality in high cardiovascular risk patients.
This occurs when there is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases.
Researchers at the University of Padua, Italy, investigated the role of oxidative stress in Fabry disease. They analyzed blood samples from 10 patients with Fabry disease and 10 healthy volunteers.
They found that levels of a specific protein involved in the production of oxidative compounds, called p22phox, were 1.9 times higher in Fabry patients as compared with controls. Also, the levels of a compound that serves as a marker of oxidation in fatty molecules, called MDA, were 1.8 times higher in Fabry patients.
Next, researchers evaluated the expression of an antioxidant, anti-inflammatory and anti-apoptotic (anti-cell death) protein called heme-oxygenase inducible isoform 1 (HO-1). On average, Fabry patients had 37% lower levels of this protein than healthy volunteers.
These results suggest that oxidative stress “occurs in Fabry disease” and that the “antioxidant defenses, such as activation of HO-1, is altered” in these patients, researchers said.
Further assessment of the activation state of a protein called MYPT-1, which occurs in response to oxidative stress and is known to be involved in vasoconstriction and cardiovascular-renal remodeling, was 17 times higher in Fabry patients.
Contrary to what researchers expected, the activation state of another oxidative stress effector protein called ERK 1/2 was found to be reduced by 40% in these patients.
However, high Gb3 levels have been associated with increased intracellular cyclic adenosine monophosphate (cAMP), an important messenger molecule in many biological processes.
Because in cardiac cells the activation of ERK1/2 is under cAMP control, elevated cAMP levels may induce a reduction in the activation of ERK1/2, thus explaining these results.
According to researchers, this study provides new evidence that “oxidative stress activation and the altered reaction to it” could be an important mechanism in Fabry disease, mediating the cardiovascular-renal remodeling experienced by patients.
“Given the small size of patients studied, an unavoidable consequence of the rare nature of Fabry disease, our conclusions should be considered preliminary,” researchers emphasized.
Additional studies are necessary to better understand the role of oxidative stress in Fabry disease, and to explore the therapeutic potential of antioxidant strategies to slow the progression of cardiac, cerebrovascular and renal damage that occurs in Fabry patients, researchers concluded.