The Anti-Thrombotic Enzyme ADAMTS13 Reduces Inflammation and the Development of Atherosclerosis In Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 367-367
Author(s):  
Anil K Chauhan ◽  
Chintan Gandhi ◽  
Mohammad Moshahid Khan ◽  
Steven R. Lentz
Keyword(s):  
Carotid Sinus ◽  
Plaque Formation ◽  
Western Diet ◽  
Chow Diet ◽  
High Fat ◽  
Lesion Area ◽  
Aortic Sinus ◽  
Male And Female ◽  
Atherosclerotic Plaque Formation ◽  
Normal Chow

Abstract Abstract 367 Background and objective: ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) plays a pivotal role in preventing spontaneous thrombosis in the microvasculature by cleaving hyperactive ultra large von Willebrand factor (ULVWF) multimers into smaller, less active multimers. Severe deficiency of ADAMTS13 in humans causes thrombotic thrombocytopenic purpura (TTP) and numerous epidemiological studies have demonstrated associations between decreased ADAMTS13 activity and adverse disease outcome in patients with systemic inflammation. It remains unknown, however, whether reduced ADAMTS13 activity plays a direct pathogenic role in inflammatory diseases or rather simply serves as an inflammation-associated marker. We hypothesized that deficiency of ADAMTS13 enhances inflammation and accelerates the development of early atherosclerotic plaques. Results: Using intravital fluorescence microscopy, we show that the number of adherent leukocytes (adherent for > 60 s) was increased approximately four-fold at the carotid sinus, a lesion prone site, of Adamts13−/−/ApoE−/− mice (Mean ± SEM = 37 ± 6) as compared to ApoE−/− mice (Mean ± SEM = 9 ± 4, P <0.01) fed a high-fat Western diet. Interestingly, intravital microscopy showed that 100% (10/10) of the Adamts13−/−/ApoE−/− mice had plaque that occluded the carotid sinus by approximately 70–80%, whereas only 20% (2/10) of the ApoE−/− mice had plaque at the carotid sinus, and the plaques were smaller in size than those in Adamts13−/−/ApoE−/− mice (P=0.0003). Next, we determined the effects of ADAMTS13 deficiency on atherosclerotic plaque formation in the aorta and aortic sinus. We compared the extent of atherosclerosis in whole aortae stained with Oil Red O and en face lesion area measured by morphometry. Both Adamts13−/−/ApoE−/− male and female mice demonstrated significantly larger lesions in the descending aorta (P<0.01), arch of the aorta (P<0.001), and total aorta (P<0.0001) compared to ApoE−/− mice fed a high-fat Western diet. Next, we quantified the corss-sectional area of lesions in the aortic sinus using the VerHoeffs/Van Gieson method. We observed a two-fold increase in the mean lesion area in the aortic sinus of both male and female Adamts13−/−/ApoE−/− mice (P<0.01) compared to ApoE−/− mice. Macrophage content (% of total lesion area), as quantitated by immunohistochemistry, was significantly elevated in the aortic root lesions of Adamts13−/−/ApoE−/− mice compared to ApoE−/− mice, suggesting that exacerbated atherosclerosis was due to increased inflammation. Adamts13−/−/ApoE−/− mice fed a normal chow diet also demonstrated accelerated atherosclerotic plaque formation compared to ApoE−/− mice. Total cholesterol and triglyceride levels were similar in Adamts13−/−/ApoE−/− and ApoE−/− mice fed a high-fat Western diet or normal chow diet. Conclusions: These findings unravel a new functional role for the anti-thrombotic enzyme ADAMTS13 in reducing excessive inflammation and plaque formation during atherosclerosis. Disclosures: Lentz: Celgene: Ownership interest; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Fibronectin Isoform Containing the Alternatively-Spliced Extra Domain A in Circulation Accelerates the Development of Atherosclerosis in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2205-2205
Author(s):  
Chintan Gandhi ◽  
Mohammad Moshahid Khan ◽  
Anil K Chauhan
Keyword(s):  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Western Diet ◽  
High Fat ◽  
Aortic Sinus ◽  
Atherosclerotic Plaque Formation ◽  
Alternatively Spliced

Abstract Abstract 2205 Background and Objective: The fibronectin isoform containing the alternatively-spliced extra domain A (EDA+-FN) is normally absent from the circulation, but plasma levels of EDA+-FN can become markedly elevated in several pathological conditions including atherosclerosis. It remains unclear in humans whether these elevated levels of EDA+-FN are actively contributing to disease pathogenesis, or rather simply serving as a marker associated with vascular stress and/or injury. Several in vitro studies suggest that EDA+-FN can activate toll-like receptor 4 (TLR4), an innate immune receptor that triggers pro-inflammatory responses We hypothesize that presence of EDA+-FN in plasma promotes inflammation and accelerates atherosclerotic plaque formation. Model and Method: We generated EDA+/+/ApoE−/− mice, which contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+-FN, and EDA−/−/ApoE−/− mice, which contain an EDA-null allele of the EDA exon and express only FN lacking EDA. ApoE−/−, EDA+/+/ApoE−/− and EDA−/−/ApoE−/− were fed a high-fat Western diet (21% fat and 0.2% cholesterol) beginning at 6 weeks until they were sacrificed at 5 months of age (i.e., 14 weeks on high-fat Western diet). We compared the extent of atherosclerosis in whole aortae, stained with Oil Red O and en face lesion area measured by morphometry, and in the cross section area of the aortic sinus using the VerHoeffs/Van Gieson stain. Results: We report that atherosclerotic plaque (% of total aorta) formation in the aorta of EDA+/+/ApoE−/− mice was increased by two-fold compared to control ApoE−/− mice (P<0.0001). Deletion of the alternatively spliced EDA domain in the ApoE−/− mice (EDA−/−/ApoE−/−) significantly reduced atherosclerotic plaque formation in the aorta (P<0.05) compared to ApoE−/− mice. Total cholesterol and triglycerides levels were similar in ApoE−/−, EDA+/+/ApoE−/− and EDA−/−/ApoE−/− mice. Similarly, atherosclerotic plaque formation was significantly increased in the aortic sinus of EDA+/+/ApoE−/− mice, intermediate in control ApoE−/− mice and reduced in EDA−/−/ApoE−/− mice (P<0.05). Additionally, we found that macrophage content, as analyzed by immunohistochemistry, was significantly elevated in the aortic root lesions of EDA+/+/ApoE−/− mice and reduced in EDA−/−/ApoE−/− mice compared to ApoE−/− mice (P<0.05). Moreover, EDA+-FN did not affect the sex-dependent regulation of atherosclerosis in ApoE−/− mice. Future experiments using EDA+/+/ApoE−/−/TLR4−/− are under progress to determine whether EDA+-FN exacerbate atherosclerosis via upregulating TLR4 signaling. Conclusions: Our findings reveal that EDA+-FN is pro-inflammatory and promotes atherosclerotic lesion formation and that monitoring plasma EDA+-FN might have prognostic value in patients at high risk for atherosclerosis. Disclosures: No relevant conflicts of interest to declare.

ADAMTS13 Reduces Vascular Inflammation and Early Development of Atherosclerosis Via VWF-Dependent Mechanism.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2178-2178
Author(s):  
Chintan Gandhi ◽  
Steven R. Lentz ◽  
Anil K Chauhan
Keyword(s):  
Vascular Inflammation ◽  
Inflammatory Cells ◽  
Neutrophil Infiltration ◽  
Western Diet ◽  
High Fat ◽  
Lesion Area ◽  
Aortic Sinus ◽  
The Mean ◽  
Deficient Mice ◽  
Early Atherosclerosis

Abstract Abstract 2178 Background and objective: The metalloprotease ADAMTS13 prevents spontaneous thrombosis in the microvasculature by cleaving hyperactive ultra large von Willebrand factor (ULVWF) multimers into smaller and less active forms. Recently, we and others have demonstrated that ADAMTS13-deficiency aggravates vascular inflammation and early atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice fed a high-fat Western diet. Although VWF is the only known substrate for ADAMTS13, it is not known if the effects of ADAMTS13 on vascular inflammation and atherosclerosis are mediated through its proteolytic effects on VWF or possibly another ADAMTS13 substrate. In this study, we determined whether the exacerbated atherosclerosis observed in the Adamts13−/−/ApoE−/− mice is dependent or independent of VWF. Model and methods: ApoE−/−, Adamts13−/−/ApoE−/−, Adamts13−/−/Vwf−/−/ApoE−/− and Vwf−/−/ApoE−/− male mice were fed a high-fat Western diet (20% fat, 0.2% cholesterol) beginning at 6 weeks of age until they were sacrificed at 4 months. We compared the extent of atherosclerosis in the cross section area of the aortic sinus using the VerHoeffs/Van Gieson stain. Inflammatory cells (neutrophils and macrophages) in the aortic lesions were quantitated by immunohistochemistry. Results: Similar to previous published reports by us and others, we found that the mean lesion area in the aortic sinus of the Adamts13−/−/ApoE−/− mice were significantly larger (mean ± SEM: 26.6 % ± 1.9 %, P<0.01) compared with ApoE−/− mice (mean ± SEM: 20.4 % ± 1.5 %). Next, we quantitated macrophage and neutrophil infiltration into lesions in the aortic sinus by immunohistochemistry. We observed significantly increased macrophages (mac-3 positive) and neutrophils (Ly6 B.2 positive) recruitment in the aortic sinus of Adamts13−/−/ApoE−/− mice compared with ApoE−/− mice. The mean lesion area in the aortic sinus of Adamts13−/−/Vwf−/−/ApoE−/− mice (mean ± SEM: 15.2 % ± 1.5 %) were similar to Vwf−/−/ApoE−/− mice (mean ± SEM: 15.6 % ± 0.9 %), suggesting that the accelerated atherosclerosis observed in ADAMTS13-deficient mice is VWF-dependent. Finally, macrophages and neutrophils recruitment in the aortic sinus of Adamts13−/−/Vwf−/−/ApoE−/− mice were similar to Vwf−/−/ApoE−/− mice, suggesting that increased vascular inflammation observed in ADAMTS13-deficient mice is also VWF-dependent. Total cholesterol and triglyceride levels were similar among groups fed a high-fat Western diet. Conclusion: These findings reveal that VWF-deficiency abrogates accelerated early atherosclerosis in ADAMTS13-deficient mice, suggesting that VWF the only relevant substrate for ADAMTS13 in murine atherosclerosis. Disclosures: Lentz: Novo Nordisk A/S: Consultancy, Investigator Other.

scholarly journals Cardiovascular function in male and female JCR:LA-cp rats: effect of high-fat/high-sucrose diet

2017 ◽  
Vol 312 (4) ◽  
pp. H742-H751 ◽  
Author(s):  
Ian Hunter ◽  
Amanda Soler ◽  
Gregory Joseph ◽  
Brenda Hutcheson ◽  
Chastity Bradford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Cardiovascular Function ◽  
Western Diet ◽  
Female Rats ◽  
Male Rats ◽  
High Fat ◽  
Male And Female ◽  
Normal Chow ◽  
High Sucrose

Thirty percent of the world population is diagnosed with metabolic syndrome. High-fat/high-sucrose (HF/HS) diet (Western diet) correlates with metabolic syndrome prevalence. We characterized effects of the HF/HS diet on vascular (arterial stiffness, vasoreactivity, and coronary collateral development) and cardiac (echocardiography) function, oxidative stress, and inflammation in a rat model of metabolic syndrome (JCR rats). Furthermore, we determined whether male versus female animals were affected differentially by the Western diet. Cardiovascular function in JCR male rats was impaired versus normal Sprague-Dawley (SD) rats. HF/HS diet compromised cardiovascular (dys)function in JCR but not SD male rats. In contrast, cardiovascular function was minimally impaired in JCR female rats on normal chow. However, cardiovascular function in JCR female rats on the HF/HS diet deteriorated to levels comparable to JCR male rats on the HF/HS diet. Similarly, oxidative stress was markedly increased in male but not female JCR rats on normal chow but was equally exacerbated by the HF/HS diet in male and female JCR rats. These results indicate that the Western diet enhances oxidative stress and cardiovascular dysfunction in metabolic syndrome and eliminates the protective effect of female sex on cardiovascular function, implying that both males and females with metabolic syndrome are at equal risk for cardiovascular disease. NEW & NOTEWORTHY Western diet abolished protective effect of sex against cardiovascular disease (CVD) development in premenopausal animals with metabolic syndrome. Western diet accelerates progression of CVD in male and female animals with preexisting metabolic syndrome but not normal animals. Exacerbation of baseline oxidative stress correlates with accelerated progression of CVD in metabolic syndrome animals on Western diet.

Microcirculatory and glycocalyx properties are lowered by high salt diet but augmented by western diet in genetically heterogeneous mice

2022 ◽  
Author(s):  
Xiangyu Zheng ◽  
Christina Deacon ◽  
Abigail J King ◽  
Daniel R Machin
Keyword(s):  
Barrier Function ◽  
Boundary Region ◽  
Microvascular Density ◽  
Western Diet ◽  
High Salt ◽  
Chow Diet ◽  
Male And Female ◽  
Female Mice ◽  
Normal Chow ◽  
Analysis System

Many individuals in industrialized societies consume a high salt, western diet, however, the effects of this diet on microcirculatory properties and glycocalyx barrier function are unknown. Young genetically heterogeneous male and female mice underwent 12 weeks of normal chow diet (NC), NC diet with 4% salt (NC4%), western diet (WD), or WD with 4% salt (WD4%). Microcirculatory properties and glycocalyx barrier function were evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. Total microvascular density summed across 4-25 μm microvessel segment diameters was lower in NC4% compared to NC and WD (P<0.05). Perfused boundary region (PBR), a marker of glycocalyx barrier function, averaged across 4-25 μm microvessel segment diameters was similar between NC and NC4%, as well as between WD and WD4% (P>0.05). PBR was lower in WD and WD4% compared to NC and NC4% (P<0.05), indicating augmented glycocalyx barrier function in WD and WD4%. There were strong, inverse relationships between PBR and adiposity and blood glucose (r=-0.44 to -0.61, P<0.05). In summary, NC4% induces deleterious effects on microvascular density, whereas WD augments glycocalyx barrier function. Interestingly, the combination of high salt, western diet in WD4% resulted in lower total microvascular density like NC4% and augmented glycocalyx barrier function like WD. These data suggest distinct microcirculatory adaptations to high salt and western diets that coincide when these diets are combined in young genetically heterogeneous male and female mice.

Metabolic in Vivo Labeling Highlights Differences of Metabolically Active Microbes from the Mucosal Gastrointestinal Microbiome between High-Fat and Normal Chow Diet

2017 ◽  
Vol 16 (4) ◽  
pp. 1593-1604 ◽  
Author(s):  
Andreas Oberbach ◽  
Sven-Bastiaan Haange ◽  
Nadine Schlichting ◽  
Marco Heinrich ◽  
Stefanie Lehmann ◽  
...  
Keyword(s):  
Chow Diet ◽  
High Fat ◽  
Gastrointestinal Microbiome ◽  
In Vivo Labeling ◽  
Normal Chow ◽  
Normal Chow Diet

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

Abstract 366: Biglycan Deficiency Does Not Affect Angiotensin Ii-induced Atherosclerosis but Promotes Aortic Aneurysms Formation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Tao Tang ◽  
Joel C Thompson ◽  
Patriticia G Wilson ◽  
Meghan H Yoder ◽  
Lisa R Tannock
Keyword(s):  
Aortic Rupture ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Western Diet ◽  
Aortic Aneurysms ◽  
Lesion Area ◽  
Abdominal Aneurysm ◽  
Aortic Sinus ◽  
Face Surface

Background Proteoglycans play a critical role in the development of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins. Of all the vascular proteoglycans, biglycan has been shown to be the one most closely associated with apolipoprotein B. Our previous studies showed that angII increases vascular biglycan content and predisposes to diet-induced atherosclerosis in Ldlr null mice. The purpose of this study was to determine whether biglycan deficiency protected against angII induced atherosclerosis in vivo. Methods and Results Bgn KO or WT mice, crossed to Ldlr null (C57B/6 background), were infused with angII (1000 ng/kg/min) or saline for 28 days followed by 6-week western diet feeding. Bgn KO mice showed no difference in atherosclerotic lesion area at either aortic sinus or en face surface. Unexpectedly, Bgn KO mice exhibited a striking mortality (77% for males and 48% for females) due to aortic rupture upon angII infusion. Thus, a lower dose of angII was then infused to mice to study atherosclerosis. There was no difference in lesion area between Bgn KO or WT mice under angII (500 ng/kg/min) infusion followed by 6-week western diet feeding or under one-year normal chow feeding without angII infusion. However, angII (500 ng/kg/min) still induced greater aortic rupture in Bgn KO mice (30% for males and 13% for females) than in WT mice (0% for both gender). Besides rupture, 7 Bgn KO mice out of 35 also developed aneurysm at mid-thoracic aorta whereas only 1 Bgn WT mouse out of 25 developed abdominal aneurysm after angII (500 ng/kg/min) infusion. Therefore, our study demonstrated that biglycan deficiency did not affect atherosclerotic lesion development, but induced a striking aneurysm phenotype upon angII infusion.

scholarly journals Effect of A Polyphenol-Rich Canarium album Extract on the Composition of the Gut Microbiota of Mice Fed a High-Fat Diet

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2188 ◽  
Author(s):  
Ning-Ning Zhang ◽  
Wen-Hui Guo ◽  
Han Hu ◽  
A-Rong Zhou ◽  
Qing-Pei Liu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
High Fat Diet ◽  
High Throughput Sequencing ◽  
Chow Diet ◽  
Microbiota Composition ◽  
High Fat ◽  
Canarium Album ◽  
Normal Chow ◽  
Gut Microbiota Composition ◽  
Medium Dose

This study investigated the influence of Canarium album extract (CAext) on intestinal microbiota composition of mice fed a high-fat diet (HFD). Kun Ming (KM) mice were fed either a normal chow diet or a HFD for six weeks. At the seventh week, HFD-fed mice were gavaged daily with saline, or a different dose of CAext for four weeks, respectively. Then, the composition of the gut microbiota was analyzed by high-throughput sequencing technology. Analysis of fecal microbial populations, grouped by phyla, showed significant increases of Firmicutes and Verrucomicrobia, but a decrease of Bacteroidetes in all CAext-fed mice. Particularly, CAext gavage in a low dose or a medium dose caused a significant increase in the proportion of Akkermansia. These findings suggested that CAext can alter the gut microbiota composition of HFD-fed mice, and had a potential prebiotic effects on Akkermansia.

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