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http://hdl.handle.net/11375/28565
Title: | Evaluating the Effects of Direct Thrombin Inhibition in a Mouse Model of Spontaneous Coronary Artery Disease and Myocardial Infarction |
Authors: | Lee, Louise (Yun Jou) |
Advisor: | Trigatti, Dr. Bernardo |
Department: | Medical Sciences (Blood and Cardiovascular) |
Publication Date: | 2023 |
Abstract: | Coronary heart disease involves atherosclerosis in coronary arteries, plaque rupture, and thrombosis, triggering myocardial infarction (MI). In commonly used mouse atherosclerosis models, plaques develop in the aorta, but not coronary arteries, and plaque rupture and thrombosis are rare. Mice lacking expression of the high-density lipoprotein receptor, scavenger receptor type B class I (SR-B1), and apolipoprotein E genes (apoE) are severely hypercholesterolemic, develop atherosclerosis spontaneously in coronary arteries, and exhibit MI and early death. This study aimed to better understand the involvement of thrombin by assessing fibrin deposition in coronary artery atherosclerosis development and MI in these mice. This was achieved by treating female and male SR-B1ko/ko/apoEko/ko mice with a diet supplemented with direct thrombin inhibitor, Dabigatran Etexilate (DE, 6 mg/g food, from 4-6 weeks of age). Clotting parameters (thrombin- antithrombin complex ELISA; thrombin generation assays) were measured using platelet-poor plasma. Atherosclerosis in the aortic sinus and coronary arteries was evaluated in cross-sections stained for lipids with oil red O and fibrin deposition in coronary arteries was evaluated by immunostaining. Myocardial fibrosis was detected by trichrome staining. Plasma cardiac Troponin-I and inflammatory cytokines IL-6, MCP-1, and TNF-α were measured by ELISA. The results showed that DE treatment reduced systemic inflammation, atherosclerotic plaque development in the aortic sinus and coronary arteries, and fibrin deposition in the atherosclerotic coronary arteries. It also reduced cardiomyocyte damage, but no changes were seen in cardiac fibrosis. In conclusion, while direct thrombin inhibition in a spontaneous coronary artery atherosclerosis murine model protected against some aspects of the disease development (coronary artery atherosclerosis, inflammation, myocardial damage markers) it did not protect against others (myocardial fibrosis). Therefore, these results highlight the complexity of the involvement of thrombin in coronary heart disease. |
URI: | http://hdl.handle.net/11375/28565 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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LEE_LOUISE (YUN JOU)_2023MAY_M.Sc..pdf | 1.87 MB | Adobe PDF | View/Open |
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