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

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%; 15weeks: 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 = 4) compared with placebo-treated mice. The pioglitazone protection was paralleled by significantly lower soluble P-selectin 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.