IN FOCUS: Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance

Abstract

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.

Murine Models of Vascular Thrombosis

“…When tested using the Rose Bengal model, purebred C57BL/6J mice form occlusion times that are significantly longer than purebred mice of the KK/HlJ strain. 52 Similar strain differences are also present between C57BL/6J, 129S1/SvImJ and other strains (Table 4). Because gene targeting is most often carried out in 129 strain-derived ES cells, and the resulting mice carrying the targeted mutation are commonly bred to the C57BL/6J mouse strain, a hybrid F1 results.…”

“…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.…”

“…16,48 -51 For example, when testing this model on mice of the KK/HlJ strain, a reduced concentration of Rose Bengal (37.5 mg/kg) had to be used to increase sensitivity to pharmacological interventions. 52 The Rose Bengal model has also been used to study thrombosis in veins 45,49 and in the microvasculature. 16 Rosen et al compared the effects of anticoagulant and antiplatelet therapies on thrombus formation after the previously described intravital laser and a Rose Bengal-mediated injury to the mouse ear vasculature.…”

AMP-Activated Protein Kinase Mediates the Antiplatelet Effects of the Thiazolidinediones Rosiglitazone and Pioglitazone

“…In agreement with these reports, rosiglitazone and pioglitazone attenuated platelet activity in in vitro and animal experiments, as well as in clinical studies (Sidhu et al, 2004;Bodary et al, 2005;Li et al, 2005;Khanolkar et al, 2008).…”

Platelet Sarcoplasmic Endoplasmic Reticulum Ca 2+ -ATPase and μ-Calpain Activity Are Altered in Type 2 Diabetes Mellitus and Restored by Rosiglitazone

“…39 However, relatively little is known about the direct effects of thiazolidinediones on platelet function other than that pioglitazone attenuates platelet hyperaggregability in rats 40 and protects against thrombosis in a mouse model of obesity and insulin resistance. 41 In humans with type 2 diabetes mellitus, troglitazone reduces platelet-dependent thrombus formation, 42 and rosiglitazone decreases the percentage of Pselectin-positive platelets in nondiabetic patients with coronary artery disease. 9 Given that rosiglitazone has been reported to increase SERCA-2 gene expression in cardiac myocytes, 17 we determined its effect on platelet SERCA-2 expression.…”