Myocardial Alterations in the Murine Model of Fabry Disease Can Be Reversed by Enzyme Replacement Therapy

Rozenfeld, Paula; Fritz, Mariana; Blanco, Paula Graciela; González, Pedro Horacio; Rinaldi, Gustavo

doi:10.1016/j.cjca.2010.12.035

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…Thus KO Fabry mice displayed a mild hypertrophic cardiomyopathy with structural and functional alteration similar to that described for the early stages of human myocardiopathies. Our results are similar to and extend the findings of Rozenfeld et al, who have described changes in passive pressure volume curves and contractility measurements in the male mouse KO model of Fabry disease, but did not document hypertrophy as assessed by cardiac weight normalized to tibial length or echo cardiographic assessment of left ventricular mass [26] .…”

Section: Discussionsupporting

confidence: 92%

“…Shayman et al have studied large vessel reactivity and pathology in this model [4] , [22] , [23] , [24] , [25] . Recent work by Rozenfeld et al has described myocardial alterations in this model, and the response to ERT given at biweekly intervals for 2 months [26] . In the present study, we found that Fabry KO male mice have bradycardia, low systemic blood pressure and mild hypertrophic cardiomyopathy when compared to the control wild-type (WT) C57BL/6J mice.…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

et al. 2012

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Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

et al. 2012

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“…However, in contrast to Fabry patients, an effect on the function of heart, kidney, and brain is completely absent or only very mild, and the life span is normal in αGalA-deficient mice. In particular, no ophthalmologic manifestations (Ohshima et al 1999 ) and no hearing loss (Noben-Trauth et al 2007 ) could be demonstrated, although some studies have reported slight sensorimotor alterations (Rodrigues et al 2009 ; Marshall et al 2010 ) and a marginal myocardial affection (Yoshimitsu et al 2006 ; Rozenfeld et al 2011 ; Nguyen Dinh Cat et al 2012 ). The latter could not be verified in our colony, possibly due to the extensive backcrossing towards the reference C57BL/6 strain and a strict breeding of all strains under identical conditions (Fig.…”

Section: Discussionmentioning

confidence: 99%

Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

et al. 2014

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Fabry disease is a monogenic X-linked lysosomal storage disease caused by α-galactosidase A (αGalA) deficiency. Enzyme replacement therapy through administration of the missing αGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction therapy for Fabry disease. Owing to the fact that αGalA-deficient humans and mice accumulate the same glycosphingolipids (i.e. globosides, galabiosylceramide and isoglobosides), αGalA-deficient mice were crossed with mice deficient in enzymes synthesizing these classes of glycosphingolipids (i.e. globotrihexosylceramide and isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of globosides was sufficient to fully abolish the storage of glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction therapy through inhibition of the synthesis of globosides and isoglobosides represents a valuable therapeutic option for Fabry disease, all the more as globosides and isoglobosides seem to be dispensable.Electronic supplementary materialThe online version of this article (doi:10.1007/s00441-014-1922-9) contains supplementary material, which is available to authorized users.

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“…При помощи своевременно начатой патогенетической терапии удает-ся добиться значительного уменьшения интенсивности нейропатической боли вплоть до ее полного исчезнове-ния [38], улучшения слуха [39], положительной динамики характеристик функции почек [40,41], сердечно-сосуди-стой системы [42,43], купирования гастроинтестиналь-ных симптомов болезни [44].…”

Section: лечение болезни фабриunclassified

Fabry Disease: Symptoms in Children and Teenagers

Кузенкова¹,

Намазова-Баранова²,

Podkletnova³

et al. 2015

Vopr. sovr. pediatr.

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Myocardial Alterations in the Murine Model of Fabry Disease Can Be Reversed by Enzyme Replacement Therapy

Cited by 7 publications

References 31 publications

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

Fabry Disease: Symptoms in Children and Teenagers

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