Projects per year
Abstract
BACKGROUND: Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. METHODS AND RESULTS: ApoE−/− mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high-fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co-transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP-1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap-to-lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. CONCLUSIONS: The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque-stabilizing effects of sodium-glucose co-transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought-after potential to stabilize atherosclerotic plaques.
Original language | English |
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Article number | e022761 |
Number of pages | 11 |
Journal | Journal of the American Heart Association |
Volume | 11 |
Issue number | 1 |
DOIs | |
Publication status | Published - 4 Jan 2022 |
Keywords
- Animal model
- Plaque instability
- Sodium glucose co-transporter 2 inhibitor
- Streptozotocin
Projects
- 1 Finished
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Targeting Nox5 to prevent atherosclerosis and aneurysm formation
Jandeleit-Dahm, K. (Primary Chief Investigator (PCI)) & Touyz, R. M. (Chief Investigator (CI))
1/01/19 → 31/12/22
Project: Research