scholarly journals Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

Metabolism ◽  
2017 ◽  
Vol 74 ◽  
pp. 32-40 ◽  
Author(s):  
Annayya R. Aroor ◽  
Guanghong Jia ◽  
Javad Habibi ◽  
Zhe Sun ◽  
Francisco I. Ramirez-Perez ◽  
...  
Keyword(s):  
Uric Acid ◽  
Inflammatory Responses ◽  
Western Diet ◽  
Vascular Stiffness

scholarly journals Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice

2017 ◽  
Vol 313 (2) ◽  
pp. R67-R77 ◽  
Author(s):  
Guido Lastra ◽  
Camila Manrique ◽  
Guanghong Jia ◽  
Annayya R. Aroor ◽  
Melvin R. Hayden ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Arterial Stiffness ◽  
Xanthine Oxidase ◽  
Aortic Stiffness ◽  
Plasma Concentrations ◽  
Western Diet ◽  
Vascular Stiffness ◽  
High Fructose ◽  
The Impact

Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.

Abstract P199: Uric Acid Promotes Vascular Stiffness, Immune Inflammatory Response and Proteinuria in Western Diet Fed Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Annayya Aroor ◽  
Guanghong Jia ◽  
Vincent G DeMarco ◽  
Javad Habibi ◽  
Zhe Sun ◽  
...  
Keyword(s):  
Uric Acid ◽  
Inflammatory Response ◽  
Vascular Inflammation ◽  
Kidney Injury ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Aortic Endothelial Cells ◽  
Force Microscopy ◽  
Atomic Force ◽  
High Fructose

Increased consumption of a diet high in fructose and fat (western diet, WD) is associated with an increase in cardiovascular disease (CVD) and kidney injury. In this regard, excess hepatic production of uric acid generated from excess fructose consumption is emerging as a risk factor for vascular stiffness, which underpins CVD and kidney injury. We hypothesized that a WD would increase uric acid levels and cardiovascular and renal xanthine oxidase (XO) activity and associated increased vascular stiffness and proteinuria. Furthermore, we proposed that inhibition of XO activity would prevent arterial stiffening and reduce proteinuria in a clinically relevant model of WD-induced CVD and renal injury. Four week-old C57BL6/J male mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without allopurinol (125mg/L), a potent XO inhibitor for 16 weeks. XO inhibition significantly attenuated WD-induced increases in plasma and urine uric acid levels and aortic XO activity (WD, 0.225 + 0.031 mU/mL WD + allopurinol, 0.097+ 0.026mU/mL, P<0.05), as well as proteinuria (WD, 20.92 + 2.66 mg/ mg creatinine, WD + allopurinol, 13.48 + 1.56 mg/mg creatinine, P<0.05). XO inhibition had no effect on increases in body weight, fat mass, and HOMA-IR promoted by the WD. Blood pressure was not different between any of the groups. Stiffness of aortic endothelial cells, extracellular matrix and vascular smooth muscle cells, as determined by atomic force microscopy, was significantly increased in WD mice and this was prevented by XO inhibition. WD induced a significant macrophage pro-inflammatory response in aorta that was significantly suppressed by XO inhibition. Collectively, these findings support the notion that increased XO activity in the vasculature and kidney and increased hepatic production of uric acid secondary to consumption of a WD promotes vascular stiffness, vascular inflammation and a maladaptive immune response that lead to vascular stiffness and kidney injury.

Chlorogenic acid supplementation ameliorates hyperuricemia, relieves renal inflammation, and modulates intestinal homeostasis

2021 ◽  
Author(s):  
Xiaofei Zhou ◽  
Bowei Zhang ◽  
Xiuli Zhao ◽  
Yongxi Lin ◽  
Jin Wang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Chlorogenic Acid ◽  
Serum Uric Acid ◽  
Inflammatory Responses ◽  
Elevated Serum ◽  
Purine Metabolism ◽  
Intestinal Homeostasis ◽  
Renal Inflammation ◽  
Acid Supplementation

Hyperuricemia (HUA) is induced by abnormal purine metabolism and elevated serum uric acid (UA) concentrations, and it is often accompanied by inflammatory responses and intestinal disorders. This study aims to...

CTRP3 protects against uric acid-induced endothelial injury by inhibiting inflammation and oxidase stress in rats

2021 ◽  
pp. 153537022110471
Author(s):  
Junxia Zhang ◽  
Xue Lin ◽  
Jinxiu Xu ◽  
Feng Tang ◽  
Lupin Tan
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Specific Inhibitor ◽  
Endothelial Damage ◽  
Endothelial Injury ◽  
Sprague Dawley ◽  
Protein Levels ◽  
And Oxidative Stress

Hyperuricemia, which contributes to vascular endothelial damage, plays a key role in multiple cardiovascular diseases. This study was designed to investigate whether C1q/tumor necrosis factor (TNF)-related protein 3 (CTRP3) has a protective effect on endothelial damage induced by uric acid and its underlying mechanisms. Animal models of hyperuricemia were established in Sprague-Dawley (SD) rats through the consumption of 10% fructose water for 12 weeks. Then, the rats were given a single injection of Ad-CTRP3 or Ad-GFP. The animal experiments were ended two weeks later. In vitro, human umbilical vein endothelial cells (HUVECs) were first infected with Ad-CTRP3 or Ad-GFP. Then, the cells were stimulated with 10 mg/dL uric acid for 48 h after pretreatment with or without a Toll-like receptor 4 (TLR4)-specific inhibitor. Hyperuricemic rats showed disorganized intimal structures, increased endothelial apoptosis rates, increased inflammatory responses and oxidative stress, which were accompanied by reduced CTRP3 and elevated TLR4 protein levels in the thoracic aorta. In contrast, CTRP3 overexpression decreased TLR4 protein levels and ameliorated inflammatory responses and oxidative stress, thereby improving the morphology and apoptosis of the aortic endothelium in rats with hyperuricemia. Similarly, CTRP3 overexpression decreased TLR4-mediated inflammation, reduced oxidative stress, and rescued endothelial damage induced by uric acid in HUVECs. In conclusion, CTRP3 ameliorates uric acid-induced inflammation and oxidative stress, which in turn protects against endothelial injury, possibly by inhibiting TLR4-mediated inflammation and downregulating oxidative stress.

Abstract 608: Uric Acid Potentially Interacts With Parathyroid Hormone To Promote Left Ventricular Diastolic Dysfunction In Mice Fed A Western Diet

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Guanghong Jia ◽  
Brian P Bostick ◽  
Javad Habibi ◽  
Annayya R. Aroor ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Uric Acid ◽  
Parathyroid Hormone ◽  
Diastolic Dysfunction ◽  
Cardiac Mri ◽  
Left Ventricular ◽  
Western Diet ◽  
P Value ◽  
Lv Diastolic Dysfunction

Hyperuricemia is frequently observed in obese people and rising obesity rates parallel increased consumption of a high-fat/high-fructose western diet (WD). Epidemiologic and clinical data suggest that serum uric acid (UA) is positively associated with serum parathyroid hormone (PTH) and may be linked with left ventricular (LV) hypertrophy and LV diastolic dysfunction. Accordingly, we hypothesized that allopurinol, a potent xanthine oxidase (XO) inhibitor, would prevent development of LV diastolic dysfunction, independent of blood pressure, by reducing the levels of UA and PTH. Four week-old C57BL6/J male mice were fed a WD and water with 125mg/L allopurinol. After 16 weeks, we assessed levels of UA, XO activity, PTH, as well as diastolic function by cardiac MRI and cardiac ultrastructure by transmission electron microscopy (TEM). Body weight and fat composition were obtained along with HOMA -IR testing for insulin resistance. Allopurinol has been show to exert no effect on blood pressure. High resolution cardiac MRI revealed diastolic dysfunction with WD feeding that was prevented by allopurinol (LV diastolic relaxation time 35.3 ms for WD, 25.4 ms for CD and 27.7 ms for WD+ allopurinol, p value <0.01; Initial filling rate 0. 28 μl/ms for WD, 0.43 μl/ms for CD and 0.42 μl/ms for WD+ allopurinol, p value <0.05). Body weight, fat mass, and HOMA-IR were increased by WD feeding but not significantly improved by allopurinol. However, allopurinol markedly decreased the WD-induced increase in heart weight associated with activation of translational S6 kinase. TEM examination of myocardial ultrastructure revealed that WD induced remodeling changes with large mitochondria with disordered cristae and increased lysosomes. The ultrastructural changes were improved with treatment by allopurinol. Furthermore, allopurinol significantly inhibited both of plasma and urine UA levels and cardiac XO activity caused by WD. Interestingly , WD increased PTH levels which were decreased in parallel with reductions in uric acid with allopurinol. These findings support the notion that increased plasma levels of UA, in concert with elevated PTH, may play a key role in LV hypertrophy and associated LV diastolic dysfunction that result from consuming a WD high in fructose and fat.

Abstract 371: DPPIV Inhibitor MK0626 Prevents Western Diet Induced Renal Injury via Suppression of Kidney Tissue Ras

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Ravi Nistala ◽  
Javad Habibi ◽  
Annayya Aroor ◽  
Melvin R Hayden ◽  
Mona Garro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Renal Injury ◽  
Sodium Excretion ◽  
The United States ◽  
Western Diet ◽  
Ang Ii ◽  
High Fructose ◽  
Dppiv Inhibitor ◽  
And Oxidative Stress

Objectives: Obesity is an independent risk factor for development and progression of renal injury. High fructose corn syrup consumption has coincided with the obesity epidemic in the United States. High fructose (60%) diets have been demonstrated to be associated with elevation in BP and worsening insulin resistance along with renal injury via increased hepatic production of uric acid. Recently, DPPIV inhibitors have been shown to improve diabetic changes and sodium excretion, effects that are beyond glycemic control. Therefore, the renal protective benefits of DPPIV inhibition in a clinically relevant Western diet fed mouse model were examined. Methods: Mice fed a high fat/high fructose (WD) diet for 16 weeks and given a DPPIV inhibitor MK0626 in their diet were examined for metabolic parameters, inflammation, kidney renin-angiotensin system (RAS) and oxidative stress. Renal injury was assessed by biochemical, immunohistological and electron microscopy techniques. In vitro , angiotensin II (Ang II) effects on OKP-PTCs were assessed for mechanism. Results: MK0626 ameliorated WD-induced increases in serum uric acid, oxidative stress and RAS. WD induced suppression of IL-10 was reversed by MK0626. There was a tendency to improve HOMA-IR by MK0626 but no effect on BP and body weights. Diet induced DPPIV activation in the plasma and kidney of WD mice was abrogated by MK0626 (~80%). WD mice were characterized by increased proteinuria (~3-fold), mesangial expansion and podocyte effacement and these changes were prevented by MK0626. In addition, the PTC endocytosis protein megalin and basilar canalicular network and mitochondrial ultrastructure abnormalities were reversed by MK0626. WD mice had decreased sodium excretion which was improved by MK0626. Ang II directly increased DPPIV activity and sodium hydrogen exchanger activity in PTCs and decreased megalin protein, which was effectively prevented by MK0626. Conclusion: Thus, WD induced increases in DPPIV activity is associated with elevations in uric acid, renal RAS, inflammation and oxidative stress which may result in renal injury. These results suggest that DPPIV inhibitors prevent WD induced renal injury and offer a novel therapy for diabetic and obesity associated renal disease.

scholarly journals 11β-hydroxysteroid dehydrogenase-1 deficiency alters the gut microbiome response to Western diet

2017 ◽  
Vol 232 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Jethro S Johnson ◽  
Monica N Opiyo ◽  
Marian Thomson ◽  
Karim Gharbi ◽  
Jonathan R Seckl ◽  
...  
Keyword(s):  
Relative Abundance ◽  
Gut Microbiome ◽  
Inflammatory Responses ◽  
Hydroxysteroid Dehydrogenase ◽  
Western Diet ◽  
Metabolic Effects ◽  
Chow Diet ◽  
The Family ◽  
The Impact

The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) interconverts active glucocorticoids and their intrinsically inert 11-keto forms. The type 1 isozyme, 11β-HSD1, predominantly reactivates glucocorticoids in vivo and can also metabolise bile acids. 11β-HSD1-deficient mice show altered inflammatory responses and are protected against the adverse metabolic effects of a high-fat diet. However, the impact of 11β-HSD1 on the composition of the gut microbiome has not previously been investigated. We used high-throughput 16S rDNA amplicon sequencing to characterise the gut microbiome of 11β-HSD1-deficient and C57Bl/6 control mice, fed either a standard chow diet or a cholesterol- and fat-enriched ‘Western’ diet. 11β-HSD1 deficiency significantly altered the composition of the gut microbiome, and did so in a diet-specific manner. On a Western diet, 11β-HSD1 deficiency increased the relative abundance of the family Bacteroidaceae, and on a chow diet, it altered relative abundance of the family Prevotellaceae. Our results demonstrate that (i) genetic effects on host–microbiome interactions can depend upon diet and (ii) that alterations in the composition of the gut microbiome may contribute to the aspects of the metabolic and/or inflammatory phenotype observed with 11β-HSD1 deficiency.

scholarly journals Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

PLoS ONE ◽  
2018 ◽  
Vol 13 (2) ◽  
pp. e0191909 ◽  
Author(s):  
Jennifer M. Rutkowsky ◽  
Linda L. Lee ◽  
Michelle Puchowicz ◽  
Mari S. Golub ◽  
Douglas E. Befroy ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Western Diet ◽  
Brain Barrier ◽  
Brain Metabolites ◽  
Blood Brain

Vascular pathophysiology of hypertension

2017 ◽  
Author(s):  
Tomasz J. Guzik ◽  
Rhian M. Touyz
Keyword(s):  
Cardiovascular Disease ◽  
Smooth Muscle ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Smooth Muscle ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Peripheral Resistance ◽  
Vascular Stiffness ◽  
Vascular Pathology

Hypertension is a multifactorial disease, in which vascular dysfunction plays a prominent role. It occurs in over 30% of adults worldwide and an additional 30% are at high risk of developing the disease. Vascular pathology is both a cause of the disease and a key manifestation of hypertension-associated target-organ damage. It leads to clinical symptoms and is a key risk factor for cardiovascular disease. All layers of the vascular wall and the endothelium are involved in the pathogenesis of hypertension. Pathogenetic mechanisms, whereby vascular damage contributes to hypertension, are linked to increased peripheral vascular resistance. At the vascular level, processes leading to change sin peripheral resistance include hyper-contractility of vascular smooth muscle cells, endothelial dysfunction, and structural remodelling, due to aberrant vascular signalling, oxidative and inflammatory responses. Increased vascular stiffness due to vascular remodelling, adventitial fibrosis, and inflammation are key processes involved in sustained and established hypertension. These mechanisms are linked to vascular smooth muscle and fibroblast proliferation, migration, extracellular matrix remodelling, calcification, and inflammation. Apart from the key role in the pathogenesis of hypertension, hypertensive vasculopathy also predisposes to atherosclerosis, another risk factor for cardiovascular disease. This is linked to increased transmural pressure, blood flow, and shear stress alterations in hypertension, as well as endothelial dysfunction and vascular stiffness. Therefore, understanding the mechanisms and identifying potential novel treatments targeting hypertensive vasculopathy are of primary importance in vascular medicine.

Dietary simple sugars alter microbial ecology in the gut and promote colitis in mice

2020 ◽  
Vol 12 (567) ◽  
pp. eaay6218 ◽  
Author(s):  
Shahanshah Khan ◽  
Sumyya Waliullah ◽  
Victoria Godfrey ◽  
Md Abdul Wadud Khan ◽  
Rajalaksmy A. Ramachandran ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
High Glucose ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Western Diet ◽  
Noncommunicable Diseases ◽  
Wild Type ◽  
Germ Free ◽  
Degrading Bacteria ◽  
Free Environment

The higher prevalence of inflammatory bowel disease (IBD) in Western countries points to Western diet as a possible IBD risk factor. High sugar, which is linked to many noncommunicable diseases, is a hallmark of the Western diet, but its role in IBD remains unknown. Here, we studied the effects of simple sugars such as glucose and fructose on colitis pathogenesis in wild-type and Il10−/− mice. Wild-type mice fed 10% glucose in drinking water or high-glucose diet developed severe colitis induced by dextran sulfate sodium. High-glucose–fed Il10−/− mice also developed a worsened colitis compared to glucose-untreated Il10−/− mice. Short-term intake of high glucose or fructose did not trigger inflammatory responses in healthy gut but markedly altered gut microbiota composition. In particular, the abundance of the mucus-degrading bacteria Akkermansia muciniphila and Bacteroides fragilis was increased. Consistently, bacteria-derived mucolytic enzymes were enriched leading to erosion of the colonic mucus layer of sugar-fed wild-type and Il10−/− mice. Sugar-induced exacerbation of colitis was not observed when mice were treated with antibiotics or maintained in a germ-free environment, suggesting that altered microbiota played a critical role in sugar-induced colitis pathogenesis. Furthermore, germ-free mice colonized with microbiota from sugar-treated mice showed increased colitis susceptibility. Together, these data suggest that intake of simple sugars predisposes to colitis and enhances its pathogenesis via modulation of gut microbiota in mice.

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