Induction of Diabetes Abolishes the Antithrombotic Effect of Clopidogrel in Apolipoprotein E-Deficient Mice

Area of Science:

• Cardiovascular Research
• Pharmacology
• Diabetes Mellitus Research

Background:

• Patients with acute coronary syndrome and diabetes mellitus (DM) often show a reduced response to clopidogrel.
• The mechanisms behind this impaired platelet inhibition are not fully understood.

Purpose of the Study:

• To investigate the antithrombotic and antiplatelet effects of clopidogrel in a mouse model of diabetes mellitus.
• To explore the potential of diabetic apolipoprotein E-deficient mice as a model for studying clopidogrel resistance.

Main Methods:

• Diabetes mellitus was induced in mice using streptozotocin (STZ).
• Antithrombotic effects were assessed using a ferric chloride (FeCl3)-induced thrombosis model in wild-type (WT), apolipoprotein E (apoE)-deficient, and diabetic apoE-deficient mice.
• Antiplatelet effects were evaluated using flow cytometry to measure platelet activation markers (glycoprotein IIb/IIIa and P-selectin).

Main Results:

• Clopidogrel's antithrombotic efficacy was significantly attenuated in diabetic apoE-deficient mice (1.9% thrombus area inhibition) compared to WT (85.5%) and apoE-deficient mice (75.0%).
• While clopidogrel fully inhibited ADP-induced platelet activation (glycoprotein IIb/IIIa expression), its effect on protease-activated receptor 4-activating peptide-induced P-selectin expression was diminished in diabetic mice.
• These findings suggest a specific impairment in clopidogrel's action on thrombin-induced platelet activation in diabetes.

Conclusions:

• Diabetic apoE-deficient mice represent a valuable model for understanding impaired clopidogrel response in patients with diabetes mellitus.
• The reduced efficacy may be partly due to diminished effects on thrombin-mediated platelet activation.