Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice

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Abstract

Objective:

Type 2 diabetes mellitus results in a procoagulant and thrombogenic state that could predispose diabetic individuals to develop venous thrombosis. We sought to determine whether diet-induced type 2 diabetes mellitus affects deep venous thrombosis (DVT) resolution in a murine model.

Methods:

C57Bl/6 mice were fed a low-fat or a high-fat diet (n = 10) for 10 weeks, after which DVT was created in the inferior vena cava (IVC) by a combination of low flow and endothelial damage. The IVC and thrombus were harvested at 1 and 2 weeks. Thrombus resolution and neovascularization were investigated through transfemoral angiography (n = 10), thrombus size (n = 4) and weight (n = 10), and nitric oxide synthase 3 immunoquantification (n = 4). Macrophage content was assessed by CD68 immunoreactivity (n = 4). The fibrinolytic system (urokinase plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]) was analyzed by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Total collagen was stained by Sirius red. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were evaluated by zymography and their expressions by Western immunoblotting (n = 6) and immunohistochemistry (n = 4).

Results:

Diabetic mice had significantly larger and heavier thrombi at 1 and 2 weeks (P< .05), threefold less neovascularization (P< .05), and 35-fold increase in macrophage content (P< .01), than control mice 2 weeks after surgery. IVC recanalization was documented in 90% of 2-week control mice and in 10% of 2-week diabetic mice (P< .01). Increased vein wall collagen and less uPA and more PAI-1 expressions with a decreased uPA/PAI-1 ratio (31%,P< .01) were documented at 2 weeks in diabetic mice. MMP-2 and MMP-9 activities and expressions were significantly increased in diabetic mice at 1 and 2 weeks (P< .05) compared with control mice.

Conclusion:

Diet-induced type 2 diabetes may impair DVT resolution through altered inflammatory, fibrinolytic, and MMP responses.

Clinical Relevance:

Little is known about the risk of venous thromboembolism in patients with type 2 diabetes mellitus, which accounts for 95% of diabetes mellitus. Deep venous thrombosis and pulmonary embolism generating post-thrombotic syndrome remain significant clinical problems, affecting approximately 200,000 to 300,000 patients per year. The current obese/diabetic mouse model and the mouse model of stasis thrombus resolution provide useful approaches for determining the effect and understanding the basic biologic mechanisms of type 2 diabetes mellitus on deep venous thrombosis resolution, as well as serving as valuable tools for evaluating therapeutic options.

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