Clopidogrel Resistance in a Murine Model of Diet-Induced Obesity Is Mediated by the Interleukin-1 Receptor and Overcome With DT-678
| Autor: | Jessica Venugopal, Yanbo Fan, Y. Eugene Chen, Yifang Sun, Chiao Guo, Daniel T. Eitzman, Jianping Li, Gong Yanjun, Haoming Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
030204 cardiovascular system & hematology Pharmacology Interleukin-1 receptor Article Mice 03 medical and health sciences 0302 clinical medicine P2Y12 Cytochrome P-450 Enzyme System Diabetes mellitus Diabetes Mellitus Animals Humans Medicine Obesity cardiovascular diseases chemistry.chemical_classification biology business.industry Receptors Interleukin-1 Cytochrome P450 Prodrug medicine.disease Clopidogrel Thrombosis Diet Disease Models Animal 030104 developmental biology Enzyme chemistry biology.protein Cardiology and Cardiovascular Medicine business circulatory and respiratory physiology medicine.drug |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.120.314146 |
| Popis: | Objective: Clopidogrel is a commonly used P2Y 12 inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel. The objective of this study is to identify the mechanism of clopidogrel resistance in a murine model of diet-induced obesity (DIO). Approach and Results: C57BL/6J mice and IL-1R −/− mice were given high-fat diet for 10 weeks to generate a murine model of diet-induced obesity. Platelet aggregation and carotid arterial thrombosis were assessed in response to clopidogrel treatment. Wild-type DIO mice exhibited resistance to antiplatelet and antithrombotic effects of clopidogrel that was associated with reduced hepatic expression of CYP genes and reduced generation of the AM. IL (Interleukin)-1 receptor-deficient DIO (IL1R −/− DIO) mice showed no resistance to clopidogrel. Lack of resistance was accompanied by increased exposure of the clopidogrel AM. This resistance was also absent when wild-type DIO mice were treated with the conjugate of the clopidogrel AM, DT-678. Conclusions: These findings indicate that antiplatelet effects of clopidogrel may be impaired in the setting of diabetes mellitus due to reduced prodrug bioactivation related to IL-1 receptor signaling. Therapeutic targeting of P2Y 12 in patients with diabetes mellitus using the conjugate of clopidogrel AM may lead to improved outcomes. |
| Databáze: | OpenAIRE |
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