α-Galactosidase A Deficiency Leads to Increased Tissue Fibrin Deposition and Thrombosis in Mice Homozygous for the Factor V Leiden Mutation

Shen, Yuechun; Bodary, Peter F.; Vargas, Fernando B.; Homeister, Jonathon W.; Gordon, David; Ostenso, Kristen A.; Shayman, James A.; Eitzman, Daniel T.

doi:10.1161/01.str.0000206442.86238.39

Cited by 25 publications

(15 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…77,78 By quantitating fibrin deposition and intravascular thrombosis, we have found that the factor V Leiden mouse has also been useful to elucidate prothrombotic phenotypes in mice that develop age-related vascular disease. 52,59,79 In addition, Bodary et al observed a significant increase in thrombotic tendency with age and fatness in mice of the KK/HlJ strain. 52 Gender differences related to thrombosis have not been well documented in animal models to date, but there are clear gender effects in partial thromboplastin time, prothrombin 80 Based on these data, it is probable that there are gender effects on thrombosis in several mouse strains.…”

Section: Westrick Et Al Murine Models Of Vascular Thrombosis 2087mentioning

confidence: 99%

Murine Models of Vascular Thrombosis

Westrick

Winn

Eitzman

2007

ATVB

Self Cite

168

160

View full text Add to dashboard Cite

Abstract-Thrombotic complications of vascular disease are the leading cause of morbidity and mortality in most industrialized countries. Despite this, safe and effective drugs targeting these complications are limited, especially in the chronic setting. This is because of the complexity of thrombosis in both arteries and veins, which is becoming increasingly evident as numerous factors are now known to affect the fate of a forming thrombus. To fully characterize thrombus formation in these settings, in vivo models are necessary to study the various components and intricate interactions that are involved. Genetic manipulations in mice are greatly facilitating the dissection of relevant pro-and antithrombotic influences. Standardized models for the study of thrombosis in mice as well as evolving techniques that allow imaging of molecular events during thrombus formation are now available. This review will highlight some of the recent developments in the field of thrombosis using mouse models and how these studies are expanding our knowledge of thrombotic disease. (Arterioscler Thromb Vasc

show abstract

Section: Westrick Et Al Murine Models Of Vascular Thrombosis 2087mentioning

confidence: 99%

Murine Models of Vascular Thrombosis

Westrick

Winn

Eitzman

2007

ATVB

Self Cite

168

160

View full text Add to dashboard Cite

show abstract

“…To date, previous studies have demonstrated Gb3 accumulation in both vascular smooth muscle (VSM) and endothelium in the vasculature of Gla‐knockout (Gla −/0 ) mice, 7,8 a murine model for Fabry disease 9 . The increased vascular accumulation of Gb3 has been associated with an increased propensity for thrombosis, 7,10 as well as increased atherogenesis, 11 both of which are associated with endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Vascular Dysfunction in the Α‐galactosidase A‐knockout Mouse Is an Endothelial Cell‐, Plasma Membrane‐based Defect

Park

Whitesall

DʼAlecy

et al. 2008

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Fabry disease results from an X-linked mutation in the lysosomal alpha-galactosidase A (Gla) gene. Defective Gla results in multi-organ accumulation of neutral glycosphingolipids (GSLs), especially in the vascular endothelium, with the major GSL accumulated being globotriaosylceramide (Gb3). Excessive endothelial Gb3 accumulation is associated with increased thrombosis, atherogenesis and endothelial dysfunction. However, the mechanism(s) by which endothelial dysfunction occurs is unclear. The purpose of the present study was to further characterize the vasculopathy associated with a murine model of Fabry disease. Vascular reactivity was performed in vessels from wild-type (Gla(+/0)) and Gla-knockout (Gla(-/0)) mice. Conscious blood pressure and heart rate were measured in Gla(+/0) and Gla(-/0) mice by telemetry. The present study demonstrates that vascular smooth muscle (VSM) contractions to phenylephrine and serotonin, but not to U46619, were blunted in Gla(-/0) mice. Endothelium-dependent contraction and receptor-mediated endothelium-dependent relaxation to acetylcholine were significantly attenuated in vessels from Gla(-/0) mice. However, receptor-independent endothelium-dependent relaxation to the calcium ionophore ionomycin remained intact in vessels from Gla(-/0) mice. Furthermore, VSM reactivity was normal in aortas from Gla(-/0) mice in the absence of endothelium. These changes in vascular function were observed without changes in whole-animal blood pressure or heart rate. These results suggest that the vasculopathy associated with Fabry disease is localized to the endothelium, despite the accumulation of GSLs throughout the vasculature.

show abstract

“…Histological evidence suggests many similarities with human Fabry disease, although some discordance is present (4,(11)(12)(13). One significant advantage of the murine model is the ability to investigate Fabry tissues such as the aorta and heart, which are generally inaccessible in clinical studies.…”

mentioning

confidence: 99%

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach

Moore¹,

Gelderman

Ferreira

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Fabry disease is a disorder of ␣-D-galactosyl-containing glycolipids resulting from a deficiency of ␣-galactosidase A. Patients have a poorly understood vascular dysregulation. We hypothesized that disease-related perturbation by using enzyme replacement therapy in the murine model of Fabry disease would provide insight into abnormal biological processes in Fabry disease. Gene expression analyses of the heart, aorta, and liver of male ␣-galactosidase A knockout mice 28 weeks of age were compared with that of WT mice. Microarray analyses were performed before and after six weekly injections of ␣-galactosidase A. Alteration of Rpgrip1 ranked highest statistically in all three organs when knockout mice were compared with WT, and its splice variants responded in a unique way to ␣-galactosidase A. Enzyme replacement therapy tended to not only normalize gene expression, e.g., reduce the overexpression of securin, but also specifically modified gene expression in each tissue examined. Following multiple comparison analysis, gene expression correlation graphs were constructed, and a priori hypotheses were examined by using structural equation modeling. This systems biology approach demonstrated multiple and complex parallel cellular abnormalities in Fabry disease. These abnormalities form the basis for informed, in a Bayesian sense, sequential, hypothesis-driven research that can be subsequently tested experimentally.glycolipids ͉ growth factor ͉ lysosomal ͉ reactive oxygen species

show abstract

α-Galactosidase A Deficiency Leads to Increased Tissue Fibrin Deposition and Thrombosis in Mice Homozygous for the Factor V Leiden Mutation

Cited by 25 publications

References 10 publications

Murine Models of Vascular Thrombosis

Murine Models of Vascular Thrombosis

Vascular Dysfunction in the Α‐galactosidase A‐knockout Mouse Is an Endothelial Cell‐, Plasma Membrane‐based Defect

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach

Contact Info

Product

Resources

About