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.


OBJECTIVE
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 = 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.
Bodary
P F
PF
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0644, USA. pfbodary@umich.edu
Vargas
F B
FB
King
S A D
SA
Jongeward
K L
KL
Wickenheiser
K J
KJ
Eitzman
D T
DT
D000818:Animals; D002339:Carotid Arteries; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005913:Glipizide / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance; D051379:Mice; D009765:Obesity / Q000150:complications*; D019007:P-Selectin / Q000097:blood; D000077205:Pioglitazone; D010975:Platelet Aggregation Inhibitors; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D045162:Thiazolidinediones; D000077205:Pioglitazone; D005913:Glipizide