Fabry Disease in Mice Is Associated With Age-Dependent Susceptibility to Vascular Thrombosis

Eitzman, Daniel T.; Bodary, Peter F.; Shen, Yuechun; Khairallah, Christian G.; Wild, Susan R.; Abe, Akira; Shaffer-Hartman, Jacqueline; Shayman, James A.

doi:10.1097/01.asn.0000043901.45141.d4

Cited by 66 publications

(55 citation statements)

References 18 publications

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“…Besides its effects on TF and TFPI, guggulsterone downregulated PAI-1 expression both in quiescent and TNF-a stimulated cells; hence, guggulsterone may be particularly beneficial in patients with diabetes mellitus. Photochemical injury was selected for examining thrombus formation because it is an established protocol for TF-dependent arterial thrombosis in vivo [5,7,8]. Guggulsterone inhibited thrombotic occlusion, indicating that it may protect from thrombus formation.…”

Section: Discussionmentioning

confidence: 99%

“…From the onset of injury, blood flow was monitored for 120 min, at which time the experiment was terminated. Occlusion was defined as flow £0.1 ml/min for at least 1 min [8]. Mice were divided into two groups: guggulsterone (oral gavage, 5 h before surgery; 100 mg/kg guggulsterone diluted in 0.5% methyl cellulose in an injection volume of 10 ml/kg), or vehicle control (0.5 % methyl cellulose).…”

Section: J Tf Activitymentioning

confidence: 99%

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Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Section: J Tf Activitymentioning

confidence: 99%

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

et al. 2008

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“…Left ventricular tissue samples from the 3-hour group were fixed in formalin solution for 24 hours, embedded in paraffin, cut into 4-m sections, and stained with hematoxylin and eosin, Carstairs, 16 and hematoxylin basic fuchsin picric acid (HBFP), 17 respectively. A microscope (Olympus-BX41 TF, Olympus Co., Tokyo, Japan) incorporated with an image analysis software (Image Pro-4, Media Cybernetics, Inc., Atlanta, GA) was used to observe the microthrombosis in the coronary arteriole.…”

Section: Light Microscopic Analysismentioning

confidence: 99%

Establishment and Characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats

Bai

et al. 2010

The American Journal of Pathology

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To establish a model of coronary thrombotic microembolism in rats, either automicrothrombotic particulates (CM group) or saline control (SHAM group) was injected into temporarily clamped aortas of male Sprague-Dawley rats. After automicrothrombotic particulate injection, serum c-troponin I and von Willebrand factor levels, the no-flow area as evaluated by Thioflavin S, myocardial leukocyte infiltration levels, myocardial expressions of tumor necrosis factor ␣ and interleukin-6, the percentage of arterioles obstructed by thrombosis, and myocardial fibrosis were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the sham group. Thus, aortic automicrothrombotic particulate injection could induce coronary microembolism in rats, and this model could be of value in improving the understanding of pathophysiology of coronary microembolism. Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndrome and during coronary interventions.1 It does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation, which has recently been identified as a potential cause of no-reflow phenomenon, myocardium ischemia, and myocardial infarctlet. Atherosclerotic embolization in the microvasculature is associated with adverse prognosis. [1][2][3][4] Research results derived from suitable experimental models of coronary microembolism would help clinicians to understand the underlying pathological mechanisms and to develop effective therapies of coronary microembolism induced by atherosclerotic embolization in the microvasculature.5 Until now, plastic microspheres ranging from 20 to 900 m in diameter were injected into the coronary microcirculation to establish the coronary microembolism models in dog, swine and sheep.6 -11 Experimental models were also made by injecting adenosine-diphosphate or catecholamine to induce platelet aggregation in coronary microcirculation in pigs.12-13 However, injecting microspheres with unique sizing would only occlude respective vessels with comparable sizes, while thrombotic debris in patients might vary greatly in sizing and affect vessels with different diameters. Models using adenosine diphosphate or catecholamine could mimic the platelet aggregation process during coronary microthrombosis but could not reflect the influences of various embolism components of atherosclerotic plaques. Therefore, established coronary microembolism models could only partly mimic the in vivo situation of coronary microthrombosis. In the present study, we showed that coronary microembolism could be induced by intraaortic injection of automicrothrombotic particulates varying in sizing in rats. Increased myocardial inflammatory cells infiltration and fibrosis as well as reduced cardiac function w...

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“…5 A mouse model of Gla deficiency has been generated by targeted disruption of the Gla gene. 6 These mice accumulate glycosphingolipids in multiple organs with age, including the large blood vessels 7,8 ; thus, they provide a useful model to study the vascular consequences of Gla deficiency. The present study was designed to test the consequences of Gla deficiency in vascular disease with a mouse model of atherosclerosis.…”

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confidence: 99%

α-Galactosidase A Deficiency Accelerates Atherosclerosis in Mice With Apolipoprotein E Deficiency

et al. 2005

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Background-␣-Galactosidase A (Gla) deficiency leads to widespread tissue accumulation of neutral glycosphingolipids and is associated with premature vascular complications such as myocardial infarction and stroke. Glycosphingolipids have been shown to accumulate in human atherosclerotic lesions, although their role in atherogenesis is unclear. Methods and Results-To determine whether Gla affects the progression of atherosclerosis, mice were generated with combined deficiencies of apolipoprotein E and Gla. At 45 weeks of age, Gla-deficient mice had developed more atherosclerosis than mice with normal Gla expression (25.1Ϯ14.0 versus 12.3Ϯ9.3 mm 2 of total lesion area, PϽ0.02). This increase in atherosclerosis was associated with the presence of increased Gb3, enhanced inducible nitric oxide synthase expression, and increased nitrotyrosine staining. Conclusions-These findings suggest that deficiency of Gla leads to increased inducible nitric oxide synthase expression and accelerated atherosclerosis. (Fabry disease) is an X-linked disorder that leads to widespread tissue accumulation of neutral glycosphingolipids with ␣-galactosyl linkages consisting primarily of globotriaosylceramide (Gb3). 1 Clinical manifestations of Fabry disease include renal failure, painful neuropathies, angiokeratoma, myocardial infarction, and stroke, which lead to premature mortality. 1 Although premature vascular complications are more common in subjects with Fabry disease, 2-4 the effect of Gla deficiency on atherogenesis is unknown. Glycosphingolipids have been shown to accumulate in atherosclerotic plaques even in subjects without Fabry disease, which suggests they may play a role in atherogenesis. 5 A mouse model of Gla deficiency has been generated by targeted disruption of the Gla gene. 6 These mice accumulate glycosphingolipids in multiple organs with age, including the large blood vessels 7,8 ; thus, they provide a useful model to study the vascular consequences of Gla deficiency. The present study was designed to test the consequences of Gla deficiency in vascular disease with a mouse model of atherosclerosis. Methods MiceTo test the consequences of Gla deficiency on vascular disease, we examined the development of lipid lesions between apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) littermate mice with genetic variation in Gla. ApoE Ϫ/Ϫ mice on the C57BL6/J background were purchased from Jackson Laboratory (Bar Harbor, Me). Gla-deficient (Gla Ϫ/0 or Gla Ϫ/Ϫ ) mice were bred from mice provided by Drs Ashok Kulkarni and Roscoe Brady (National Institutes of Health, Bethesda, Md). The "0" in Gla Ϫ/0 denotes the absence of the second X chromosome of the male mice in this X-linked disease. These mice were backcrossed at least 6 generations to the C57BL6/J strain before being bred to Analysis of AtherosclerosisAt 45 weeks of age, mice were euthanized via exsanguination while under intraperitoneal pentobarbital anesthesia (100 mg/kg). The mice were perfused with phosphate-buffered saline and fixed with formalin with a 25-gauge needle, insert...

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Fabry Disease in Mice Is Associated With Age-Dependent Susceptibility to Vascular Thrombosis

Abstract: Abstract. Fabry disease is an X-linked lysosomal storage disorder due to deficiency of ␣-galactosidase A (GLA) activity that results in the widespread accumulation of neutral glycosphingolipids. Renal failure, neuropathy, premature myocar-

Cited by 66 publications

References 18 publications

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Establishment and Characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats

α-Galactosidase A Deficiency Accelerates Atherosclerosis in Mice With Apolipoprotein E Deficiency

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