TY - JOUR
T1 - Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes-Induced Atherosclerotic Plaque Instability
AU - Chen, Yung Chih
AU - Jandeleit-Dahm, Karin
AU - Peter, Karlheinz
N1 - Funding Information:
Chen is supported by a Heart Foundation Future Leader Fellowship (No: 102068). Peter is supported by the National Health and Medical Research Council L3 Investigator Fellowship. The work was partially supported by the National Health and Medical Research Council project grants (APP1163233, APP1159460, CIA Jandeleit-Dahm).
Publisher Copyright:
© 2021 The Authors.
PY - 2022/1/4
Y1 - 2022/1/4
N2 - 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.
AB - 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.
KW - Animal model
KW - Plaque instability
KW - Sodium glucose co-transporter 2 inhibitor
KW - Streptozotocin
UR - http://www.scopus.com/inward/record.url?scp=85123320821&partnerID=8YFLogxK
U2 - 10.1161/JAHA.121.022761
DO - 10.1161/JAHA.121.022761
M3 - Article
C2 - 34970931
AN - SCOPUS:85123320821
SN - 2047-9980
VL - 11
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 1
M1 - e022761
ER -