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

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 Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

Journal of the American Heart Association ◽

10.1161/jaha.121.022761 ◽

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.

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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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The circulating levels of CTRP5 and the ratio of CTRP1 to CTRP5 plasma levels are significant predictors for cIMT value in patients with type 2 diabetes

10.21203/rs.3.rs-20710/v1 ◽

2020 ◽

Author(s):

Ziba Majidi ◽

Abolfazl Omidifar ◽

Solaleh Emamgholipour ◽

Soheil Rahmani Fard ◽

Hossein Poustchi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Plasma Levels ◽

Human Subjects ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Thickness Measurement ◽

Enzyme Linked Immunosorbent Assay ◽

Visceral Adiposity Index ◽

Circulating Levels

Abstract Background There is growing evidence that C1qTNF-related protein (CTRP) family has crucial role in physiology and pathophysiology of metabolic disorders such as Type 2 Diabetes (T2D) and obesity. We sought to identify the association of CTRP1 and CTRP5 circulating levels with various obesity parameters such as visceral adipose tissue (VAT) thickness, visceral adiposity index (VAI) and with carotid intima-media thickness (cIMT) in patients with T2D and healthy subjects. Methods This case- control study recruited 42 T2D patients and 42 healthy adults (all men). cIMT and VAT thickness measurement were performed using an Accuvix XQ ultrasound. Circulating CTRP1 and CTRP5 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results CTRP-1 and CTRP1/CTRP5 ratio were markedly higher in patients with T2D compared to controls (p < 0001 and p < 0004 respectively). Interestingly, binominal logistic regression revealed that higher circulating level of CTRP1 was associated with presence of T2D (odds ratio [OR]: 13203.554 [95% CI: 65.186-2674407.708]; P=.000). When considering the study population as a whole, CTRP1 circulating levels were correlated with WHR, VAT and HOMA-IR. In addition, we observed that the ratio of CTRP1 to CTRP5 plasma levels (β = 0.648, P=0.005) and CTRP5 circulating levels (β = 0.4 44, P=0.049) are significant predictors for cIMT value. Conclusions Our results indicated that CTRP1 and CTRP5 concentrations were correlated with atherosclerosis in human subjects and these adipokines might have a causal role for cardiometabolic risk in type 2 diabetes disease

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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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Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

Journal of Neuroinflammation ◽

10.1186/s12974-021-02145-8 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Sarinnapha M. Vasunilashorn ◽

◽

Long H. Ngo ◽

Simon T. Dillon ◽

Tamara G. Fong ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Plasma Levels ◽

Inflammatory Markers ◽

Brain Barrier ◽

Markers Of Inflammation ◽

Blood Brain ◽

Csf Levels ◽

The Relationship

Abstract Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids. Results Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

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