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J Mol Med (Berl) ; 89(1): 65-74, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20941593

ABSTRACT

Fabry disease is a multisystem X-linked disorder resulting from α-galactosidase A (α-GalA) gene mutations leading to the accumulation of globotriaosylceramide mainly in endothelium compromising heart, kidney, and brain. In Fabry patients, progressive renal failure is frequently treated with angiotensin I-converting enzyme (ACE) inhibitors. We were interested in the possible interactions between ACE inhibitors therapy and the only causative therapy for Fabry disease, the enzyme replacement therapy (ERT) using recombinant human α-GalA (rhα-GalA). Our results suggest that ACE activity was significantly inhibited in plasma of Fabry patients and the blood pressure level decreased just after ERT (at the end of the rhα-GalA infusion). Interestingly, 2 weeks later, ACE activity was significantly upregulated and the plasma levels of angiotensin II increased in the patients treated with rhα-GalA following the elevations of ACE activity. The same inhibitory effect on ACE activity was also observed in rats after rhα-GalA infusion. Furthermore, ACE activity in CHO cells transfected with the human ACE was inhibited dose and time-dependently by rhα-GalA. In vitro, the incubation of plasma from healthy volunteers with rhα-GalA significantly reduced ACE activity. Finally, rhα-GalA also inhibited ACE activity and released galactose residues from purified rabbit lung ACE dose-dependently. In summary, our results suggest that rhα-GalA interacts with ACE and inhibits its activity, possibly by removing the galactose residues from the enzyme. This modulation might have profound impact on the clinical outcome of Fabry patients treated with rhα-GalA.


Subject(s)
Blood Pressure/drug effects , Fabry Disease/enzymology , Gene Expression Regulation, Enzymologic/drug effects , Peptidyl-Dipeptidase A/metabolism , alpha-Galactosidase/pharmacology , Adolescent , Adult , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/blood , Animals , CHO Cells , Cricetinae , Cricetulus , Fabry Disease/drug therapy , Female , Humans , Male , Middle Aged , Models, Animal , Peptidyl-Dipeptidase A/blood , Rabbits , Rats , Rats, Wistar , Recombinant Proteins/pharmacology , Young Adult , alpha-Galactosidase/therapeutic use
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