Urate-Lowering Drugs and Prevention of Cardiovascular Disease

Borghi, Claudio; Desideri, Giovambattista

doi:10.1161/hypertensionaha.115.06531

Cited by 57 publications

(38 citation statements)

References 12 publications

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“…Inhibition of UA through targeting of xanthine oxidase has been found to decrease vascular dysfunction and improve cardiovascular function recent (21). The current study further found that high dose UA directly impaired NO generation in cultured human umbilical vein ECs, suggesting that hyperuricemia impairs vascular function by a mechanism of inhibition of NO production.…”

Section: Discussionsupporting

confidence: 69%

The role of hyperuricemia on vascular endothelium dysfunction

Zhen

Gui

2017

Biomedical Reports

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Abstract. Hyperuricemia appears to be associated with an increased risk for cardiovascular disease and associated mortality. Population epidemiological data support a causal link between hyperuricemia and cardiovascular disease. Endothelium injury could be one of the potential mechanisms in hyperuricemia-induced cardiovascular disease. However, the specific role of uric acid (UA) in the impairment of vascular relaxation and its signal transduction pathway has not been examined. The authors investigated the role of UA on vascular relaxation, nitric oxide (NO) production and expression of proinflammatory cytokines. Brachial flow-mediated dilation and nitroglycerine-mediated dilation were measured by B-mode ultrasound with 10 megahertz linear-array transducer from 21 patients with hyperuricemia and 16 control subjects. Human umbilical vein endothelial cells (ECs) were incubated with UA (5-15 mg/dl) with or without nuclear factor (NF)-κB inhibitor II. Hyperuricemia inhibited brachial flow-mediated dilation. While UA significantly inhibited NO expression with time course-and dose-dependent manner in the cultured ECs, 10 mg/dl UA also increased expression of inflammation cytokine interleukin (IL)-6, IL-8 and tumor necrosis factor-α in vitro. These abnormalities were associated with UA-induced activation of transcription factor NF-κB. Furthermore, NF-κB inhibitor II prevented UA-induced reduction of NO and increased inflammation cytokines. These data suggested hyperuricemia-induced endothelium injury and vascular dysfunction by a reduction of NO and expression of inflammatory cytokines through the NF-κB pathway. IntroductionHyperuricemia has been linked to cardiovascular disease (CVD) recent since it is regarded as an independent risk factors in the contribution of CVD including vascular disease, hypertension, metabolic syndrome and renal disease (1). Generally, uric acid (UA) levels >7 mg/dl in males and >6 mg/dl in females are considered as hyperuricemia in a clinical aspect (2). Risk factors for hyperuricemia include alcohol consumption, intake of high fat diet and refined carbohydrate, and the medicines of diuretics and angiotensin converting enzyme antagonists (1,2). Population epidemiological studies support the notion that there is a causal link between hyperuricemia and CVD. For example, Rotterdam (3) and a NHANES I study (4) found that there is an association between high levels of UA and myocardial infarctions and cardiovascular death even after adjustment for related factors such as age, dyslipidemia and obesity. Multiple center studies also suggested that hyperuricemia prompts hypertension and coronary heart disease, as well as vascular diseases such as cerebrovascular disease, preeclampsia, vascular dementia and kidney disease (5,6). Some of the potential pathophysiological mechanisms have been investigated to explain the association between UA and vascular injury. One study suggested that high dose UA significantly increased angiotensin II and oxidative stress in cultured endothelial cells (ECs) and this ...

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Section: Discussionsupporting

confidence: 69%

The role of hyperuricemia on vascular endothelium dysfunction

Zhen

Gui

2017

Biomedical Reports

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“…Although uric acid has been implicated in mediating glomerular injury in several preclinical studies, including ours in WD-fed male mice [6, 34], the role of XO activation in ECs has also been implicated in endothelial cortical stiffness through glycocalyx polymerization and shedding [35–37]. Indeed, glycocalyx shedding is one of the mechanisms by which glomerular filtration barrier is compromised resulting in proteinuria [38, 39].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Objective Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Materials/Methods Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16 weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. Results XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Conclusions Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration.

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“…Starting from these evidences, it is intriguing to speculate that in the presence of hyperuricemia, the diffusion of UA through blood-brain barrier could increase the concentrations of UA in CSF to levels that might exert detrimental effects on cells biology by promoting the onset and/or progression of neuronal damage. An alteration of integrity of blood-brain barrier, which can occur in patients with AD (Bowman et al, 2010) as well as in the presence of cerebrovascular disease (Kalaria et al, 2016) or high blood pressure levels (Choi et al, 2015;Fan et al, 2015;Borghi and Desideri, 2016) could further contribute to achieve potentially "toxic" levels of UA in CSF. Indeed, the alteration of blood-brain barrier integrity is associated with a further increase of UA levels in CSF (Bowman et al, 2010).…”

Section: Journal Of Cellular Physiologymentioning

confidence: 99%

“…According to this, in our study, UA was able to potentiate the neurotoxic effects of hydrogen peroxide also at the lowest tested concentration (20 mM) while UA alone was unable to affect cell viability at this dose. In this regard, it is worth mentioning that xanthine oxidase is a source of reactive oxygen species and as such when hyperactivated may contribute to oxidative stress thus potentiating cells injury promoted by UA (Borghi et al, 2015;Borghi and Desideri, 2016). Thus, its is intriguing to speculate that the same UA concentration achieved in biological fluid could differently influence cells biology depending of the main determinant of such concentration, that is, increased production by xanthine oxidase or impaired renal excretion.…”

Section: Journal Of Cellular Physiologymentioning

confidence: 99%

“…Thus, its is intriguing to speculate that the same UA concentration achieved in biological fluid could differently influence cells biology depending of the main determinant of such concentration, that is, increased production by xanthine oxidase or impaired renal excretion. Indeed, the hyperactivity of xanthine oxidase from on site increases the generation of UA while concomitantly potentiate the ability of UA to promote cell damage (Borghi and Desideri, 2016). Interestingly, it has been recently demonstrated a dosedependent response to xanthine oxidase inhibitors in relation to vascular brain damage (MacIsaac et al, 2016) which suggests and influential role of this metabolic pathway on brain vessels integrity which, in turn, influences UA concentration in CSF (Bowman et al, 2010).…”

Section: Journal Of Cellular Physiologymentioning

confidence: 99%

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Uric Acid Amplifies Aβ Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro

Desideri

Gentile

Antonosante

et al. 2016

Journal Cellular Physiology

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There is still a considerable debate concerning whether uric acid is neuroprotective or neurotoxic agent. To clarify this topic, we tested the effects of uric acid on neuronal cells biology by using differentiated SHSY5Y neuroblastoma cells incubated with amyloid β to reproduce an in vitro model of Alzheimer's disease. The incubation of cells with uric acid at the dose of 40 µM or higher significantly reduced cell viability and potentiated the proapoptotic effect of amyloid β. Finally, uric acid enhanced the generation of 4-hydroxynonenal and the expression of PPARβ/δ promoted by amyloid β, indicating a prooxidant effects. In conclusion, uric acid could exert a detrimental influence on neuronal biology being this influence further potentiated by the concomitant exposure to neurotoxic stimuli. This effect is evident for uric acid concentrations close to those achievable in cerebrospinal fluid in presence of mild hyperuricemia thus suggesting a potential role of uric acid in pathophysiology of cognitive dysfunction. These effects are influenced by the concentrations of uric acid and by the presence of favoring conditions that commonly occur in neurodegenerative disorders and well as in the aging brain, including increased oxidative stress and exposure to amyloid β. J. Cell. Physiol. 232: 1069-1078, 2017. © 2016 Wiley Periodicals, Inc.

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Urate-Lowering Drugs and Prevention of Cardiovascular Disease

Cited by 57 publications

References 12 publications

The role of hyperuricemia on vascular endothelium dysfunction

The role of hyperuricemia on vascular endothelium dysfunction

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

Uric Acid Amplifies Aβ Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro

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