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

Abstract

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.

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

“…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.…”

α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

“…Whereas these mice accumulate a-galactosyl GSLs in tissues and develop microscopic lesions characteristic of Fabry disease, they live a normal lifespan and do not display altered blood and urine findings suggestive of organ dysfunction (7). Although subtle differences in cardiovascular function have been reported (8), the lack of litterand strain-matched control mice makes interpretation of these studies difficult. In an attempt to elicit a more robust phenotype, 1 group overexpressed Gb3 synthase in Gla KO mice (9).…”

Sphingosine 1-phosphate induced by hypoxia increases the expression of PAI-1 in HepG2 cells via HIF-1α

“…In thrombotic thrombocytopenic purpura, thrombus formation is facilitated and red blood cells are mechanically destroyed. In these diseases or animal models PAI-1 is shown to be increased (29,(33)(34)(35), suggesting that excessive S1P can increase PAI-1 and shift the fibrinolytic balance toward thrombosis.…”