The Tandem Stenosis Mouse Model: Towards Understanding, Imaging and Preventing Atherosclerotic Plaque Instability and Rupture

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.

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Tandem Stenosis to Induce Atherosclerotic Plaque Instability in the Mouse

Methods in Molecular Biology - Methods in Mouse Atherosclerosis ◽

10.1007/978-1-4939-2929-0_23 ◽

2015 ◽

pp. 333-338 ◽

Cited By ~ 4

Author(s):

Yung Chih Chen ◽

Jennifer Rivera ◽

Karlheinz Peter

Keyword(s):

Atherosclerotic Plaque ◽

Plaque Instability ◽

Tandem Stenosis

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PT342 A novel hemodynamics based mouse model as a tool for discovery of genes and micro-rna that are associated with atherosclerotic plaque instability/rupture

Global Heart ◽

10.1016/j.gheart.2014.03.2068 ◽

2014 ◽

Vol 9 (1) ◽

pp. e233

Author(s):

Yung-Chih Chen ◽

Karlheinz Peter

Keyword(s):

Mouse Model ◽

Atherosclerotic Plaque ◽

Micro Rna ◽

Plaque Instability

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A Novel Mouse Model of Atherosclerotic Plaque Instability for Drug Testing and Mechanistic/Therapeutic Discoveries Using Gene and MicroRNA Expression Profiling

Circulation Research ◽

10.1161/circresaha.113.301562 ◽

2013 ◽

Vol 113 (3) ◽

pp. 252-265 ◽

Cited By ~ 92

Author(s):

Yung-Chih Chen ◽

Anh Viet Bui ◽

Jeannine Diesch ◽

Richard Manasseh ◽

Christian Hausding ◽

...

Keyword(s):

Mouse Model ◽

Atherosclerotic Plaque ◽

Expression Profiling ◽

Drug Testing ◽

Microrna Expression ◽

Plaque Instability

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Plasma levels of trimethylamine-N-oxide can be increased with ‘healthy’ and ‘unhealthy’ diets and do not correlate with the extent of atherosclerosis but with plaque instability

Cardiovascular Research ◽

10.1093/cvr/cvaa094 ◽

2020 ◽

Cited By ~ 7

Author(s):

Yen Chin Koay ◽

Yung-Chih Chen ◽

Jibran A Wali ◽

Alison W S Luk ◽

Mengbo Li ◽

...

Keyword(s):

Mouse Model ◽

Plasma Levels ◽

Human Subjects ◽

Calcium Score ◽

Intima Media Thickness ◽

Direct Oxidation ◽

Plaque Instability ◽

Markers Of Inflammation ◽

Major Interest ◽

Tandem Stenosis

Abstract Aims The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. Methods and results Plasma TMAO increased in mice on ‘unhealthy’ high-choline diets and notably also on ‘healthy’ high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE−/− and Ldlr−/− mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. Conclusions Dietary-induced changes in the microbiome, of both ‘healthy’ and ‘unhealthy’ diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.

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

10.21203/rs.3.rs-540987/v1 ◽

2021 ◽

Author(s):

Yung-Chih Chen ◽

Karen Jandeleit-Dahm ◽

Karlheinz Peter

Keyword(s):

Mouse Model ◽

Sglt2 Inhibitor ◽

Atherosclerotic Plaques ◽

Plaque Instability ◽

Glucose Levels ◽

Nadph Oxidase 4 ◽

Plaque Stabilization ◽

Tandem Stenosis ◽

Plaque Destabilization ◽

The Right

Abstract Aims/hypothesis: Diabetes is known to accelerate the progression of 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 (TS) mouse model, which reflects plaque instability and rupture as seen in patients, can be applied to study the effects of diabetes and its respective therapeutic approaches on plaque instability/rupture. Methods: ApoE -/- mice at 7 weeks of age were injected with streptozotocin (STZ) for 5 consecutive days. 5 weeks after STZ injection, mice were surgically subjected to TS in the right carotid artery and fed with a high-fat diet for an additional 7 weeks. To validate this newly developed animal model, administration of the interventional drug dapagliflozin was provided via drinking water (25 mg/kg) 3 days after TS surgery. Results: Diabetic mice showed an increase in the size of unstable atherosclerotic plaques in the TS model. Plaque instability markers such as MCP-1, CD68, and necrotic core (NC) size were significantly increased. Mice treated with the sodium glucose co-transporter 2i (SGLT2i) dapagliflozin demonstrated attenuated glucose levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap-to-lesion ratios, and significant upregulation of plaque NADPH oxidase 4 (NOX4) expression. Conclusions/interpretation: The TS mouse model in combination with the application of STZ 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 SGLT2i. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing anti-diabetic drugs for their highly sought-after potential to stabilize atherosclerotic plaques.

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Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice

Royal Society Open Science ◽

10.1098/rsos.171447 ◽

2018 ◽

Vol 5 (3) ◽

pp. 171447 ◽

Cited By ~ 5

Author(s):

R. Xing ◽

A. M. Moerman ◽

Y. Ridwan ◽

M. J. Daemen ◽

A. F. W. van der Steen ◽

...

Keyword(s):

Shear Stress ◽

Wall Shear Stress ◽

Mouse Model ◽

Atherosclerotic Plaque ◽

Proximal Part ◽

Plaque Progression ◽

Plaque Composition ◽

Spatial Changes ◽

Temporal And Spatial ◽

Wall Shear

Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE −/− mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition.

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