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ACE activity is modulated by the enzyme α-galactosidase A

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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.

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Sources of funding

This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2008/06676-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Probral CAPES/DAAD, 239/06), Deutsche Akademische Austauschdienst (DAAD/PROBRAL) and Deutsche Forschungsgemeinschaft (BA 1374/16-1). Elice Carneiro Batista was supported by a doctoral fellowship from CAPES PROEX (Nr.33009015001).

Disclosures

María Verónica Muñoz Rojas works as medical manager, Genzyme do Brasil. Fabrazyme is manufactured by Genzyme for Fabry disease patient treatment.

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Correspondence to João Bosco Pesquero.

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Batista, E.C., Carvalho, L.R., Casarini, D.E. et al. ACE activity is modulated by the enzyme α-galactosidase A. J Mol Med 89, 65–74 (2011). https://doi.org/10.1007/s00109-010-0686-2

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  • DOI: https://doi.org/10.1007/s00109-010-0686-2

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