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

2021 ◽  
Author(s):  
Yung‐Chih Chen ◽  
Karin Jandeleit‐Dahm ◽  
Karlheinz Peter
Keyword(s):  
Mouse Model ◽  
Sglt2 Inhibitor ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Nadph Oxidase 4 ◽  
Plaque Stabilization ◽  
Tandem Stenosis ◽  
Plaque Destabilization ◽  
The Right ◽  
Accelerate Atherosclerosis

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.

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

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.

Statin treatment is associated with reduced toll-like receptor 4 immunohistochemical expression on carotid atherosclerotic plaques: a novel effect of statins

Vascular ◽  
2011 ◽  
Vol 19 (6) ◽  
pp. 320-326 ◽  
Author(s):  
Athanasios Katsargyris ◽  
Chris Klonaris ◽  
Sotirios Tsiodras ◽  
Elias Bastounis ◽  
Athanasios Giannopoulos ◽  
...  
Keyword(s):  
Carotid Plaque ◽  
Statin Treatment ◽  
Atherosclerotic Plaques ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Immunohistochemical Expression ◽  
Toll Like Receptor 4 ◽  
Over Expression ◽  
Plaque Stabilization ◽  
Plaque Destabilization

Toll-like receptor 4 (TLR4) has been recently implicated in inflammatory pathways involved in carotid plaque destabilization. Given that statins have plaque stabilization and inflammation reduction effects, we investigated whether TLR4 expression on carotid atherosclerotic plaques correlates with statin intake. Carotid atherosclerotic plaques were obtained on 140 patients (preoperative statin intake, n = 70). TLR4 immunohistochemical expression was investigated in endothelial cells (ECs), macrophages (MACs) and smooth muscle cells (SMCs) of carotid atheroma. TLR4 positivity, over-expression and intensity of immunostaining were compared in statin versus no-statin users. The results of this study showed that statin users had a significantly lower expression of TLR4 in ECs ( P = 0.02, 0.001, 0.006 for TLR4 positivity, increased intensity and over-expression, respectively). Similarly, TLR4 positivity was less pronounced in carotid plaque MACs of statin users ( P = 0.03). No carotid specimen with increased EC TLR4 intensity or over-expression was observed among statin users. The prevalence of any cerebrovascular accident was 61.4% in the ‘no statin’ versus 18.6% in the ‘statin’ group (odds ratio for statin use: 0.14, 95% CI: 0.07–0.31, P < 0.001). In conclusion, statin treatment is associated with attenuated TLR4 expression on human carotid atherosclerotic plaques and a reduced risk of carotid-related cerebrovascular events. TLR4 may potentially mediate statins' plaque stabilization effects. Further investigation is necessary.

scholarly journals 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

2020 ◽  
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.

scholarly journals Acetazolamide and SGLT2 inhibitor as potent drugs for a patient with diabetes mellitus and worsening chronic lymphedema: A case report

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Hajime Kataoka
Keyword(s):  
Body Weight ◽  
Fluid Collection ◽  
Sglt2 Inhibitor ◽  
Chloride Concentration ◽  
Tissue Fluid ◽  
Fat Deposits ◽  
Serum Chloride ◽  
The Right ◽  
Chronic Lymphedema

Treatment of lymphedema using a pharmacologic approach is reported to have limited efficacy. Here, I report a patient with type 2 diabetes (T2DM) and acute worsening of her chronic lymphedema, in whom treatment with acetazolamide and a sodiumglucose cotransporter-2 inhibitor (SGLT2i) effectively improved the lymphedema. A 94-year-old woman, who was treated for T2DM, hyperlipidemia, and hypertension for 17 years at my hospital presented to the emergency room because of acute worsening of her chronic right leg lymphedema with increased swelling, tightness, and dull aching. A pharmacologic approach was used to treat her worsening lymphedema. Acetazolamide 500 mg/d was administered to treat the acute tissue fluid collection in the right lymphedematous leg. Ten days later, the patient’s body weight was markedly reduced by 3.2 kg, pitting in the right leg was markedly improved, and the circumference of right limb was decreased. On day 11, the glucose-lowering agent vildagliptin was switched to the SGLT2i empagliflozin 10 mg/d. On day 70, her body weight had decreased further by 2.8 kg, and the circumference of her right limb was greatly reduced compared with that under treatment with acetazolamide. Her serum chloride concentration was increased after treatment, but her hemoglobin and hematocrit values did not change during the study period. In conclusion, acetazolamide and an SGLT2i have acute diuretic effects for draining the excess tissue fluid in the lymphedematous limb without vascular contraction by enhancing vascular tonicity. Additionally, an SGLT2i may have chronic effects for reducing fat deposits in the lymphedematous limb.

scholarly journals Different Approaches in Therapy Aiming to Stabilize An Unstable Atherosclerotic Plaque

2021 ◽  
Vol 22 (9) ◽  
pp. 4354
Author(s):  
Michal Kowara ◽  
Agnieszka Cudnoch-Jedrzejewska
Keyword(s):  
Atherosclerotic Plaque ◽  
Clinical Problem ◽  
Myocardial Infarctions ◽  
Matrix Remodeling ◽  
Plaque Erosion ◽  
Plaque Stabilization ◽  
Regulation Of Metabolism ◽  
Alternative Approaches ◽  
Unstable Atherosclerotic Plaque ◽  
Plaque Destabilization

Atherosclerotic plaque vulnerability is a vital clinical problem as vulnerable plaques tend to rupture, which results in atherosclerosis complications—myocardial infarctions and subsequent cardiovascular deaths. Therefore, methods aiming to stabilize such plaques are in great demand. In this brief review, the idea of atherosclerotic plaque stabilization and five main approaches—towards the regulation of metabolism, macrophages and cellular death, inflammation, reactive oxygen species, and extracellular matrix remodeling have been presented. Moreover, apart from classical approaches (targeted at the general mechanisms of plaque destabilization), there are also alternative approaches targeted either at certain plaques which have just become vulnerable or targeted at the minimization of the consequences of atherosclerotic plaque erosion or rupture. These alternative approaches have also been briefly mentioned in this review.

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

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e115728 ◽  
Author(s):  
Zahra Mohri ◽  
Ethan M. Rowland ◽  
Lindsey A. Clarke ◽  
Amalia De Luca ◽  
Véronique Peiffer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Arterial Wall ◽  
Plaque Instability

Simvastatin Reduces Expression and Activity of Lipoprotein-Associated Phospholipase A2 in the Aorta of Hypercholesterolaemic Atherosclerotic Rabbits

2009 ◽  
Vol 37 (4) ◽  
pp. 1029-1037 ◽  
Author(s):  
Z Qiao ◽  
J Ren ◽  
H Chen
Keyword(s):  
Atherosclerotic Lesion ◽  
Statin Treatment ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Local Inflammatory Response ◽  
Plaque Instability ◽  
Significant Difference

Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to atherosclerotic plaque instability and subsequent sudden coronary death. Statins are associated with decreased stroke risk and may improve stability of atherosclerotic plaques. The present study investigated the effect of simvastatin on expression of Lp-PLA2 levels in atherosclerotic plaques and on Lp-PLA2 activity in atherosclerotic aortas. Rabbits were a fed chow (control group) or a high-cholesterol diet (atherosclerosis group) for 12 weeks. An additional group on the high-cholesterol diet received simvastatin (5 mg/kg per day) for the last 4 weeks (simvastatin group). Lp-PLA2 activity in plasma and atherosclerotic aortas was significantly higher in the atherosclerosis group than in the control group and, consistent with this, abundant Lp-PLA2 protein was detected in plaques in the atherosclerosis group. Simvastatin significantly reduced Lp-PLA2 activity in plasma and aorta tissue, and reduced Lp-PLA2 protein level in atherosclerotic plaques. Whereas there was no significant difference in total atherosclerotic lesion area between simvastatin and atherosclerosis groups, simvastatin significantly reduced macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Thus, statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques. This was associated with attenuation of the local inflammatory response and improved plaque stability.

scholarly journals ShenLian Extract Enhances TGF-β Functions in the Macrophage-SMC Unit and Stabilizes Atherosclerotic Plaques

2021 ◽  
Vol 12 ◽  
Author(s):  
Li Liu ◽  
Qi Li ◽  
Jie Yin ◽  
Zheng Zhao ◽  
Lidong Sun ◽  
...  
Keyword(s):  
High Performance ◽  
Macrophage Polarization ◽  
Neutralizing Antibody ◽  
Immunofluorescent Staining ◽  
Phenotypic Switching ◽  
Atherosclerotic Plaques ◽  
M2 Macrophage ◽  
Inflammatory Microenvironment ◽  
Phenotypic Transformation ◽  
The Right

Background/Aim: Macrophage polarization and phenotypic switching of smooth muscle cells (SMCs) are multi-faceted events dominating atherosclerosis (AS) progression. TGF-β was proved to been one of the bridge on the crosstalk between macrophage and SMC. ShenLian (SL) was extracted from a potent anti-atherosclerotic formula. However, its exact mechanism rebalancing inflammatory microenvironment of AS remain largely unknown. Within the entirety of macrophage and SMC, this study investigated the pharmacological effects of SL on stabilizing atherosclerotic plaques.Methods: The main components of SL were examined by high performance liquid chromatography. Co-culture and conditioned medium models of macrophage/SMC interactions were designed to identify the relationship between macrophage polarization and switching of SMC phenotypes. Flow cytometry, immunofluorescent staining, RT-PCR, western blotting, and ELISA were used to determine the expression of molecules relating to AS progression. An atherosclerosis animal model, established by placing a perivascular collar on the right common carotid artery in ApoE−/− mice, was used to investigate whether TGF-β is the key molecular mediator of SL in crosstalk between macrophage and SMC. Plaque size was defined by nuclear magnetic resonance imaging. Key markers related to phenotypic transformation of macrophage and SMC were determined by immunohistochemical staining.Results: Results revealed that, accompanied by rebalanced M2 macrophage polarization, SL supported SMC phenotypic transformation and functionally reconstruct the ECM of plaques specifically in macrophage-SMC co-cultural model. Molecularly, such activity of SL closely related to the activation of STAT3/SOCS3 pathway. Furthermore, in co-culture system, up-regulation of α-SMA induced by SL could neutralized by 1D11, a TGF-β neutralizing antibody, indicating that SL mediated Macrophage-SMC communication by enhancing TGF-β. In the AS model constructed by ApoE−/− mice, effects of SL on phenotypic transformation of macrophage and SMC has been well verified. Specific blocking of TGF-β largely attenuated the aforementioned effects of SL.Conclusion: Our findings highlighted that TGF-β might be the responsive factor of SL within macrophage and SMC communication. This study revealed that crosstalk between macrophage and SMC forms a holistic entirety promoting atherosclerotic plaque stability.

Sign in / Sign up

Export Citation Format

Share Document