Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes-Induced Atherosclerotic Plaque Instability

• Published in: Journal of the American Heart Association Vol. 11; no. 1; p. e022761
• Main Authors: Chen, Yung-Chih, Jandeleit-Dahm, Karin, Peter, Karlheinz
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 04.01.2022; Wiley
• Subjects: animal model; Animals; Benzhydryl Compounds; Brief Communication; Constriction, Pathologic; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Disease Models, Animal; Glucose; Glucosides; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Mice; plaque instability; Plaque, Atherosclerotic - pathology; Sodium - metabolism; sodium glucose co‐transporter 2 inhibitor; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Streptozocin - therapeutic use; streptozotocin; plaque instability; sodium glucose co‐transporter 2 inhibitor; streptozotocin; animal model
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/jaha.121.022761

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.