Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

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

British Journal of Pharmacology ◽

10.1111/bph.15356 ◽

2020 ◽

Author(s):

Jonathan Noonan ◽

Alex Bobik ◽

Karlheinz Peter

Keyword(s):

Mouse Model ◽

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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PC224. Aerobic Exercise Attenuates Arterial Wall Remodeling in a Smooth Muscle Cell LRP1-Deficient Mouse Model

Journal of Vascular Surgery ◽

10.1016/j.jvs.2019.04.405 ◽

2019 ◽

Vol 69 (6) ◽

pp. e266

Author(s):

Brittany O. Aicher ◽

Selen Muratoglu ◽

Areck A. Ucuzian ◽

Dudley Strickland

Keyword(s):

Smooth Muscle ◽

Mouse Model ◽

Smooth Muscle Cell ◽

Aerobic Exercise ◽

Muscle Cell ◽

Arterial Wall ◽

Deficient Mouse

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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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Effect of atherosclerosis on thermo-mechanical properties of arterial wall and its repercussion on plaque instability

International Journal of Cardiology ◽

10.1016/j.ijcard.2007.08.087 ◽

2009 ◽

Vol 132 (3) ◽

pp. 444-446 ◽

Cited By ~ 3

Author(s):

G.V. Guinea ◽

J.M. Atienza ◽

P. Fantidis ◽

F.J. Rojo ◽

A. Ortega ◽

...

Keyword(s):

Mechanical Properties ◽

Arterial Wall ◽

Plaque Instability

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Structural modifications in the arterial wall during physiological aging and as a result of diabetes mellitus in a mouse model: Are the changes comparable?

Diabetes & Metabolism ◽

10.1016/j.diabet.2010.08.005 ◽

2011 ◽

Vol 37 (2) ◽

pp. 106-111 ◽

Cited By ~ 8

Author(s):

G. Prévost ◽

H. Bulckaen ◽

C. Gaxatte ◽

E. Boulanger ◽

G. Béraud ◽

...

Keyword(s):

Diabetes Mellitus ◽

Mouse Model ◽

Arterial Wall ◽

Physiological Aging ◽

Structural Modifications

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Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis Compared with Healthy Subjects: A Case-Control Study

The Journal of Rheumatology ◽

10.3899/jrheum.120617 ◽

2012 ◽

Vol 39 (12) ◽

pp. 2261-2266 ◽

Cited By ~ 16

Author(s):

ALPER M. VAN SIJL ◽

KATJA VAN DEN HURK ◽

MIKE J.L. PETERS ◽

VOKKO P. VAN HALM ◽

GIEL NIJPELS ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Healthy Subjects ◽

Arterial Wall ◽

Alternative Pathway ◽

Wall Stress ◽

Arterial Remodeling ◽

Plaque Instability ◽

Increased Risk ◽

Carotid Arterial

Objective.Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, but mechanisms behind this increased risk have not been fully elucidated. Carotid arterial remodeling is the change of structural properties in response to hemodynamic or metabolic factors aimed at keeping wall stress within certain limits. This process might become maladaptive when stress on the arterial wall increases beyond these limits. We investigated whether maladaptive carotid arterial remodeling is present in RA compared with control subjects.Methods.The 2 cohorts were 96 patients with RA and 274 healthy subjects, who were investigated cross-sectionally. Carotid intima-media thickness (cIMT) and interadventitial diameter (IAD) were assessed by B-mode carotid ultrasonography. Lumen diameter (LD), circumferential wall stress (CWS), and circumferential wall tension (CWT) were calculated. Linear regression analyses were used to investigate the association between presence of RA and carotid arterial remodeling.Results.Compared with healthy subjects, RA was associated with a 0.40 mm (9.3%) greater LD, 0.41 mm (7.8%) greater IAD, 10% higher CWS, and 8% higher CWT. The groups had comparable cIMT. Associations remained similar after exclusion of patients with prior CV disease and after adjustment for demographic factors and CV risk factors.Conclusion.RA is associated with maladaptive outward carotid arterial remodeling. These results are relevant because maladaptive outward remodeling is associated with plaque instability and rupture. These results indicate an alternative pathway, beyond the traditional CV risk factors, in RA that amplifies the CV 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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