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...

Background-Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes.

See also Smyth SS, Jennings JL. PPARc agonists: a new strategy for antithrombotic therapy. This issue, pp 2147-8.Summary. Background: As arterial thrombosis accounts for the vast majority of cardiovascular complications in obese, insulin resistant patients, we hypothesized that improving insulin sensitivity may be effective in reducing the thrombotic response following vascular injury. Objectives: We investigated the effect of the thiazolidinedione drug, pioglitazone, on the thrombotic response to injury in obese, insulin resistant mice. Methods: Insulin-resistant, obesity-prone mice (KK strain) were treated with pioglitazone, placebo, or the sulfonylurea compound, glipizide, for 2.5 weeks and then subjected to photochemical injury of the carotid artery. Results: KK mice have a significant increase in adiposity (7 weeks: 25.6%; 15 weeks: 34.4%; P < 0.0001) and thrombotic tendency (7 weeks: 21.2 ± 1.9 min; 15 weeks: 13.7 ± 1.7 min; P < 0.01) with age. Pioglitazone provided significant protection from thrombosis at both time points, prolonging the time to occlusive thrombosis by 40% and 68%, at 7 and 15 weeks of age, respectively (P < 0.05). Similarly, following a diet-challenge to promote diabetes, pioglitazone provided protection from occlusive thrombus formation (Placebo: 11.3 ± 1.0 min; Pioglitazone: 22.3 ± 3.9 min; P < 0.05). However, despite a salient effect of glipizide on the hyperglycemia of the mice, there was no effect on the time to occlusive thrombus formation (13.2 ± 0.9 min, n ¼ 4) compared with placebo-treated mice. The pioglitazone protection was paralleled by significantly lower soluble Pselectin and platelet P-selectin expression providing evidence of an antiplatelet effect. Conclusions: We conclude that pioglitazone treatment provides protection against arterial thrombosis in an obese, insulin resistant, prothrombotic mouse model.

Background— Factor V Leiden (FVL) is a common genetic risk factor for vascular thrombosis in humans. Fabry disease, an X-linked lysosomal storage disorder attributable to α-galactosidase A (GLA) deficiency, is associated with premature vascular events that may be thrombotic in nature. Methods and Results— To examine a potential interaction between FvL and Gla deficiency in vivo, we analyzed tissue fibrin deposition in mice carrying combined mutations in FvL and Gla . Gla deficiency markedly increased tissue fibrin deposition in mice carrying the FvL mutation (0.33±0.03%; n=7) compared with FvL mutation (0.14±0.02%; n=10; P <0.0005). Conclusions— These observations demonstrate a synergistic interaction between Gla deficiency and FvL toward tissue fibrin deposition in mice. Concomitant mutations in these genes may increase the penetrance of vascular thrombotic events in humans.

of soluble P-and E-selectins in vivo is dependent on expression of P-selectin glycoprotein ligand-1. J Thromb Haemost 2007; 5: 599-603.Summary. Background: Factors contributing to the generation of soluble P-and E-selectins remain unclear. Results: This work demonstrates that mice lacking P-selectin glycoprotein ligand-1 (Psgl-1) are deficient in soluble P-selectin (sP-sel), which is due to a defective binding interaction between PSGL-1 and P-sel, because mice lacking a(1,3)-fucosyltransferase-VII are also deficient in sP-sel. Psgl-1 )/) mice are also deficient in soluble E-selectin (sE-sel) indicating that leukocyte interactions with endothelial cells lead to the generation of sE-sel. The generation of sE-sel requires an interaction between PSGL-1 and P-sel, as deficiency of sE-sel is observed in both Psgl-1and P-sel )/) mice. Bone marrow transplantation from Psgl-1 )/)to Psgl-1 +/+ mice leads to deficiency of sP-sel and sE-sel in recipient mice, establishing the importance of bone marrowderived PSGL-1 toward the generation of sP-sel and sE-sel. Bone marrow transplantation from P-sel )/) to P-sel1 +/+ mice does not lead to a significant reduction in sP-sel, confirming the importance of the endothelium toward the liberation of sP-sel. Conclusion: sP-sel and sE-sel reflect an interaction between leukocyte PSGL-1 and endothelial P-sel.

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