Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation.

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9-derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. METHODS: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57-75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3-122] vs. 25.7 [13.4-45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. CONCLUSIONS: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

Influence of xanthine oxidoreductase inhibitor, topiroxostat, on body weight of diabetic obese mice.

Plasma xanthine oxidoreductase (XOR) activity is high in metabolic disorders such as diabetic mellitus, obesity, or overweight. Thus, this study investigated whether the XOR inhibitor, topiroxostat, affected body weight. Male db/db mice were fed standard diets with or without topiroxostat for 4 weeks. Body weight and food intake were constantly monitored, along with monitoring plasma biochemical markers, including insulin and XOR activity. Additionally, hepatic hypoxanthine and XOR activity were also documented. Single regression analysis was performed to determine the mechanism. Topiroxostat treatment suppressed weight gain relative to the vehicle without any impact on food intake. However, the weight of fat pads and hepatic and muscle triglyceride content did not change. Topiroxostat decreased the plasma uric acid and increased hepatic hypoxanthine in response to the inhibition of XOR activity. Plasma ketone body and free fatty acid were also increased. Moreover, fat weight was weakly associated with plasma XOR activity in the diabetic state and was negatively associated with ketone body by topiroxostat. These results suggested that topiroxostat amplified the burning of lipids and the salvage pathway, resulting in predisposing the body toward catabolism. The inhibition of plasma XOR activity may contribute to weight loss.

Uric acid shown to contribute to increased oxidative stress level independent of xanthine oxidoreductase activity in MedCity21 health examination registry.

Uric acid has both antioxidant and pro-oxidant properties in vitro by scavenging and production of reactive oxygen species (ROS). This cross-sectional study examined whether uric acid possesses effects on oxidative stress under physiological conditions independent of xanthine oxidoreductase (XOR), which is involved in uric acid and ROS production. Serum uric acid level was measured, while plasma XOR activity was determined using our high-sensitive assay in 192 participants (91 males, 101 females) who underwent health examinations and were not taking an antihyperuricemic agent. For antioxidant potential and oxidative stress level, biological antioxidant potential (BAP) and derivative of reactive oxygen metabolites (d-ROMs) in serum, respectively, were measured. Median uric acid level and plasma XOR activity were 5.6 mg/dL and 26.1 pmol/h/mL, respectively, and BAP and d-ROMs levels were 2112.8 µmol/L and 305.5 Carr U, respectively. Multivariable regression analyses revealed no significant association of serum uric acid level with BAP level, whereas serum uric acid level showed a significant association with d-ROMs level independent of plasma XOR activity (p = 0.045), which was prominent in females (p = 0.036; p for interaction = 0.148). Uric acid might contribute to increased oxidative stress independent of XOR activity by increasing ROS production, without affecting ROS scavenging, especially in females.

Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes.

Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM.Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from Nov 15, 2017.

Greater coronary lipid core plaque assessed by near-infrared spectroscopy intravascular ultrasound in patients with elevated xanthine oxidoreductase: a mechanistic insight.

Elevated serum uric acid level was reportedly associated with greater coronary lipid plaque. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine metabolism and believed to play an important role in coronary atherosclerosis. However, the relation of XOR to coronary lipid plaque and its mechanism are unclear. Patients with stable coronary artery disease undergoing elective percutaneous coronary intervention under near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) guidance were prospectively enrolled. They were divided into three groups according to serum XOR activities: low, normal, and high. Coronary lipid core plaques in non-target vessels were evaluated by NIRS-IVUS with lipid core burden index (LCBI) and a maximum LCBI in 4 mm (maxLCBI4mm). Systemic endothelial function and inflammation were assessed with reactive hyperemia index (RHI) and high-sensitivity C-reactive protein, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. Of 68 patients, 26, 31, and 11 were classified as low, normal, and high XOR activity groups. LCBI (474.4 ± 171.6 vs. 347.4 ± 181.6 vs. 294.0 ± 155.9, p = 0.04) and maxLCBI4mm (102.1 ± 56.5 vs. 65.6 ± 48.5 vs. 55.6 ± 37.8, p = 0.04) were significantly higher in high XOR group than in normal and low XOR groups. Although RHI was significantly correlated with body mass index, diabetes, current smoking, and high-density lipoprotein cholesterol, no relation was found between XOR activity and RHI. There were also no relations between XOR activity and C-reactive protein, neutrophil-to-lymphocyte ratio, or platelet-to-lymphocyte ratio. In conclusion, elevated XOR activity was associated with greater coronary lipid core plaque in patients with stable coronary artery disease, without significant relations to systemic endothelial function and inflammation.

Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment.

AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short-term glycemic control treatment. MATERIALS AND METHODS: We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. RESULTS: At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4-1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. CONCLUSIONS: A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross-sectionally, and also across treatment during hospitalization.

Characteristics of Patients with an Abnormally Decreased Plasma Xanthine Oxidoreductase Activity in Acute Heart Failure Who Visited the Emergency Department.

BACKGROUND: The factors associated with a low plasma xanthine oxidoreductase (XOR) activity were not elucidated in patients with acute heart failure (AHF). METHODS: Two-hundred and twenty-nine AHF patients who visited the emergency department were prospectively analyzed. AHF patients were divided into 3 groups according to the plasma XOR quartiles (Q1 = low-XOR group [n = 57], Q2/Q3 = middle-XOR group [n = 115], and Q4 = high-XOR group [n = 57]). The prognostic nutritional index (PNI) and the controlling nutritional status (CONUT) score were evaluated. RESULTS: The multivariate logistic regression model showed that the nutritional status (PNI: OR 1.044, 95% CI 1.000-1.088; CONUT: OR 3.805, 95% CI 1.158-12.498), age, and serum creatinine level were independently associated with a low plasma XOR activity. The Kaplan-Meier curve showed a significantly lower incidence of heart failure events in the low-XOR group than in the middle + high-XOR group (hazard ratio, HR 1.648, 95% CI 1.061-2.559). In particular, a low XOR activity with an increased serum creatinine level (>1.21 mg/dL) was independently associated with heart failure events (HR 1.937, 95% CI 1.199-3.130). CONCLUSION: A low plasma XOR activity was associated with malnutrition, renal dysfunction, and aging in AHF. A low XOR activity complicated with renal dysfunction leads to adverse long-term outcomes.

Plasma xanthine oxidoreductase (XOR) activity in patients who require cardiovascular intensive care.

Hyperuricemia is known to be associated with adverse outcomes in cardiovascular intensive care patients, but its mechanisms are unknown. A total of 569 emergency department patients were prospectively analyzed and assigned to intensive care (ICU group, n = 431) or other departments (n = 138). Uric acid (UA) levels were significantly higher in the intensive care patients (6.3 [5.1-7.6] mg/dl vs. 5.8 [4.6-6.8] mg/dL). The plasma xanthine oxidoreductase (XOR) activity in the ICU group (68.3 [21.2-359.5] pmol/h/mL) was also significantly higher than that in other departments (37.2 [15.1-93.6] pmol/h/mL). Intensive care patients were divided into three groups according to plasma XOR quartiles (Q1, low-XOR, Q2/Q3, normal-XOR, and Q4, high-XOR group). A multivariate logistic regression model showed that lactate (per 1.0 mmol/L increase, OR 1.326; 95%, CI 1.166-1.508, p < 0.001) and the Acute Physiology and Chronic Health Evaluation II score (per 1.0 point increase, OR 1.095, 95% CI 1.034-1.160, p = 0.002) were independently associated with the high-XOR group. In-hospital mortality was significantly higher in the high-XOR group (n = 28, 26.2%) than in the normal- (n = 11, 5.1%) and low- (n = 9, 8.3%) XOR groups. The high-XOR group (vs. normal-XOR group) was independently associated with the in-hospital mortality (OR 2.934; 95% CI 1.170-7.358; p = 0.022). Serum UA levels and plasma XOR activity were high in patients admitted to intensive care. The enhanced XOR activity may be one of the mechanisms under which hyperuricemia was associated with adverse outcomes in patients requiring cardiovascular intensive care.

Association of plasma xanthine oxidoreductase activity with blood pressure affected by oxidative stress level: MedCity21 health examination registry.

Xanthine oxidoreductase (XOR) inhibitor administration reduces uric acid and reactive oxygen species (ROS) production, and also lowers blood pressure (BP). However, the associations of plasma XOR activity, uric acid level, and oxidative stress levels with BP remain unclear. This cross-sectional study included 156 subjects (68 males, 88 females) registered in the MedCity21 health examination registry without anti-hypertensive or anti-hyperuricemic agent administration. Plasma XOR activity was measured using our highly sensitive novel assay, which is unaffected by uric acid in the sample. BP was also determined, and serum uric acid and derivative of reactive oxygen metabolites (d-ROMs) levels were simultaneously measured. Median plasma XOR activity, serum uric acid, d-ROMs, and mean arterial pressure (MAP) values were 25.7 pmol/h/mL, 5.4 mg/dL, 305 Carr U, and 89.0 mmHg, respectively. Multiple regression analysis showed that plasma XOR activity (ß = 0.211, p = 0.019), but not serum uric acid (ß = 0.072, p = 0.502), was significantly associated with MAP. In subjects with lower but not higher d-ROMs level, an independent association of plasma XOR activity with MAP was observed (ß = 0.428, p = 0.001 and ß = 0.019, p = 0.891, respectively; p for interaction = 0.046). XOR may contribute to the pathophysiology of higher BP through ROS but not uric acid production, especially in patients with lower oxidative stress.

Relation of Plasma Xanthine Oxidoreductase Activity to Coronary Lipid Core Plaques Assessed by Near-Infrared Spectroscopy Intravascular Ultrasound in Patients With Stable Coronary Artery Disease.

Previous studies reported that elevated serum uric acid level was associated with greater coronary lipid plaque. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine metabolism and is believed to play important roles in coronary atherosclerosis. However, the relation between XOR and coronary lipid plaque is unclear. Patients with stable coronary artery disease who underwent elective percutaneous coronary intervention under near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) guidance were prospectively included. They were divided into 3 groups according to plasma XOR activities based on a previous report: low, normal, and high. Quantitative coronary angiography and gray-scale IVUS were analyzed. The primary end point was coronary lipid plaques in a nontarget vessel assessed by NIRS-IVUS with lipid core burden index (LCBI) and maximum LCBI in 4 mm (maxLCBI4mm). Out of 68 patients, 26, 31, and 11 patients were classified as low, normal, and high XOR activity groups. Quantitative coronary angiography demonstrated that the high XOR activity group had longer lesion length, smaller minimum lumen diameter, and higher percentage of diameter stenosis in a nontarget vessel among the 3 groups. Gray-scale IVUS analysis also showed smaller lumen area in the high XOR activity group than the others. LCBI (102.1 ± 56.5 vs 65.6 ± 48.5 vs 55.6 ± 37.8, p = 0.04) and maxLCBI4mm (474.4 ± 171.6 vs 347.4 ± 181.6, 294.0 ± 155.9, p = 0.04) in a nontarget vessel were significantly higher in the high XOR group than in the normal and low groups. In conclusion, elevated XOR activity was associated with coronary lipid-rich plaque in a nontarget vessel in patients with stable coronary artery disease.

Differential regulation of hypoxanthine and xanthine by obesity in a general population.

AIMS/INTRODUCTION: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. MATERIALS AND METHODS: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. RESULTS: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. CONCLUSIONS: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

Xanthine oxidoreductase activity correlates with vascular endothelial dysfunction in patients with type 1 diabetes.

AIMS: Xanthine oxidoreductase (XOR) is an enzyme regulating uric acid synthesis and generation of reactive oxygen species. Several studies suggested relationship between XOR and atherosclerotic diseases; however, few previous studies have directly examined the relationship between XOR and vascular endothelial dysfunction in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the relationship between XOR activity and vascular endothelial function in patients with T1DM. METHODS: Seventy-one patients with T1DM participated in the study and underwent assessments, including plasma XOR activity and flow-mediated dilation (FMD), to measure vascular endothelial function. RESULTS: The natural logarithm value of XOR activity (ln-XOR) was 3.03 ± 0.99 pmol/h/mL, and FMD was 5.5% ± 2.4%. FMD was inversely and significantly correlated with ln-XOR (correlation coefficient: r = - 0.396, P < 0.001), UA (r = - 0.252, P = 0.034), and asymmetric dimethylarginine (ADMA) (r = - 0.414, P < 0.001). ln-XOR showed positive correlation with HbA1c (r = 0.292, P = 0.013), ALT (r = 0.658, P < 0.001), and ADMA (r = 0.363, P = 0.002). Stepwise multiple regression analysis showed that ln-XOR (standard partial regression coefficient: ß = - 0.254, P = 0.018) was an independent explanatory variable of FMD. CONCLUSIONS: The results of this study showed for the first time that XOR activity is associated with glycemic control in patients with T1DM and that XOR activity is associated with vascular endothelial dysfunction.

Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry.

Background We developed a novel high-sensitive assay for plasma xanthine oxidoreductase (XOR) activity that is not affected by the original serum uric acid level. However, the association of plasma XOR activity with that level has not been fully examined. Methods This cross-sectional study included 191 subjects (91 males, 100 females) registered in the MedCity21 health examination registry. Plasma XOR activity was determined using our assay for plasma XOR activity with [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Serum levels of uric acid and adiponectin, and visceral fat area (VFA) obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. Results The median values for uric acid and plasma XOR activity were 333 µmol/L and 26.1 pmol/h/mL, respectively. Multivariable linear regression analysis showed a significant and positive association of serum uric acid level (coefficient: 26.503; 95% confidence interval: 2.06, 50.945; p = 0.035) with plasma XOR activity independent of VFA and HOMA-IR, and also age, gender, alcohol drinking habit, systolic blood pressure, estimated glomerular filtration rate (eGFR), glycated hemoglobin A1c, triglyceride, and adiponectin levels. The "gender*XOR activity" interaction was not significant (p = 0.91), providing no evidence that gender modifies the relationship between plasma XOR activity and serum uric acid level. Conclusions Plasma XOR activity was found to be positively associated with serum uric acid level independent of other known confounding factors affecting that level, including gender difference, eGFR, adiponectin level, VFA, and HOMA-IR.

Annual change in plasma xanthine oxidoreductase activity is associated with changes in liver enzymes and body weight.

Xanthine oxidoreductase (XOR), an enzyme of uric acid formation from hypoxanthine and xanthine, is recognized as a source of oxidative stress. Plasma activity of XOR has been reported to be a biomarker of metabolic disorders associated with obesity, liver dysfunction, insulin resistance, hyperuricemia and adipokines. We investigated longitudinal change in plasma XOR activity, which was determined by using mass spectrometry and liquid chromatography to detect [13C2, 15N2]-uric acid using [13C2, 15N2]-xanthine as a substrate, in 511 subjects (male/female: 244/267) of the Tanno-Sobetsu Study in the years 2016 and 2017. Plasma XOR activity in a basal state was significantly higher in men than in women, but no significant sex difference was observed in annual change in plasma XOR activity. Annual change in plasma activity of XOR was positively correlated with changes in each parameter, including body weight (r = 0.203, p < 0.001), body mass index, diastolic blood pressure, aspartate transaminase (AST) (r = 0.772, p < 0.001), alanine transaminase (r = 0.647, p < 0.001), γ-glutamyl transpeptidase, total cholesterol, triglycerides, uric acid, fasting glucose and HbA1c. Multivariate regression analysis demonstrated that change in AST and that in body weight were independent predictors of change in plasma XOR activity after adjustment of age, sex and changes in each variable with a significant correlation without multicollinearity. In conclusion, annual change in plasma XOR activity is independently associated with changes in liver enzymes and body weight in a general population. Improvement of liver function and reduction of body weight would decrease plasma XOR activity and its related oxidative stress as a therapeutic strategy.

Plasma xanthine oxidoreductase activity in patients with decompensated acute heart failure requiring intensive care.

AIMS: Plasma xanthine oxidoreductase (XOR) activity during the acute phase of acute heart failure (AHF) requires further elucidation. METHODS AND RESULTS: One hundred eighteen AHF patients and 231 control patients who attended a cardiovascular outpatient clinic were prospectively analysed. Blood samples were collected within 15 min of admission from AHF patients (AHF group) and control patients who visited a daily cardiovascular outpatient clinic (control group). Plasma XOR activity was compared between the two groups, and factors independently associated with extremely elevated XOR activity were identified using a multivariate logistic regression model. Plasma XOR activity in the AHF group (median, 104.0 pmol/h/mL; range, 25.9-423.5 pmol/h/mL) was significantly higher than that in the control group (median, 45.2 pmol/h/mL; range, 19.3-98.8 pmol/h/mL). The multivariate logistic regression model showed that serum uric acid (per 1.0 mg/dL increase, odds ratio: 1.280; 95% confidence interval: 1.066-1.536; P = 0.008) and lactate levels (per 1.0 mmol/L increase, odds ratio: 1.239; 95% confidence interval: 1.040-1.475; P = 0.016) were independently associated with high plasma XOR activity (>300 pg/h/mL) during the acute phase of AHF. CONCLUSIONS: Plasma XOR activity was extremely high in patients with severely decompensated AHF. This would be associated with a high lactate value and would eventually lead to hyperuricaemia in patients with AHF.

Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm.

Increased reactive oxygen species (ROS) contributes to the development of endothelial dysfunction, which is involved in coronary artery spasm (CAS). Xanthine oxidoreductase (XOR) plays a pivotal role in producing both uric acid and ROS. However, the association between plasma XOR activity and CAS has not been elucidated. The aim of this study was to investigate whether plasma XOR activity is associated with CAS. We measured XOR activity in 104 patients suspected for CAS, who presented without significant coronary artery stenosis and underwent intracoronary acetylcholine provocation tests. CAS was provoked in 44 patients and they had significantly higher XOR activity as compared with those without CAS. The patients were divided into three groups based on the XOR activity. The prevalence rate of CAS was increased with increasing XOR activity. A multivariate logistic regression analysis showed that the 3rd tertile group exhibited a higher incidence of CAS as compared with the 1st tertile group [odds ratio (OR) 6.9, P = 0.001) and the 2nd tertile group (OR 3.2, P = 0.033) after adjustment for conventional CAS risk factors, respectively. The C index was significantly improved by the addition of XOR activity to the baseline model based on CAS risk factors. Furthermore, the 3rd tertile group had the highest incidence of severe spasm defined as total obstruction, flow-limiting stenosis, diffuse spasm, multivessel spasm, and/or lethal arrhythmia. This is a first report to elucidate the association of plasma XOR activity with CAS. Increased plasma XOR activity is significantly associated with CAS.

Independent links between plasma xanthine oxidoreductase activity and levels of adipokines.

AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catalyzes uric acid formation in the purine metabolism, is involved in an increase in reactive oxygen species. Plasma XOR activity has been shown to be associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia and insulin resistance. MATERIALS AND METHODS: The association between plasma XOR activity, measured by using liquid chromatography and mass spectrometry, and levels of adipokines, including adiponectin, fatty acid-binding protein 4 (FABP4) and fibroblast growth factor 21 (FGF21), was investigated in 282 participants (male/female: 126/156) of the Tanno-Sobetsu Study who were not taking medication. RESULTS: Women had lower plasma XOR activity than did men. Smoking habit was associated with increased activity. Plasma XOR activity was positively correlated with concentrations of FABP4 (r = 0.192, P < 0.001) and FGF21 (r = 0.208, P < 0.001), homeostasis model assessment of insulin resistance as an index of insulin resistance and uric acid, and was negatively correlated with adiponectin level (r = -0.243, P = 0.001). Multivariate regression analyses showed that levels of adiponectin, FABP4 and FGF21 were independent determinants of plasma XOR activity after adjusting age, sex, uric acid and homeostasis model assessment of insulin resistance. With additional adjustment of smoking habit, the level of FABP4, but not that of adiponectin or FGF21, remained as an independent predictor of plasma XOR activity. CONCLUSIONS: Plasma XOR activity was independently associated with levels of adipokines in a general population of individuals not taking medication.

Relationship between Xanthine Oxidoreductase Redox and Oxidative Stress among Chronic Kidney Disease Patients.

Xanthine oxidase (XO), an isoform of xanthine oxidoreductase (XOR), is thought to increase the cardiovascular burden among chronic kidney disease (CKD) patients via oxidative radical production. Plasma XOR redox, which is characterized by the ratio of XO to total XOR, changes under different oxidative conditions associated with kidney dysfunction. However, the relationship between plasma XOR redox and oxidative stress (OS) is unclear. Thus, we aimed to clarify whether OS is related to XOR redox. We used the redox state of human serum albumin (HSA) as a marker to investigate the status of OS in CKD patients. HSA is composed of human mercaptoalbumin (HMA), which possesses not oxidized cysteine residues, reversibly oxidized human nonmercaptoalbumin-1 (HNA-1), and strongly oxidized human nonmercaptoalbumin-2 (HNA-2). The subjects included 13 nondialysis patients (7 males and 6 females) with varying degrees of kidney function. We found that ƒ(HMA) was negatively (R = -0.692, P = 0.0071) and ƒ(HNA-1) was positively (R = 0.703, P = 0.0058) correlated with plasma XO/XOR. ƒ(HNA-2) showed no correlation with XO/XOR (R = 0.146, P = 0.6412), indicating that plasma XOR redox is not related to the irreversible oxidation of HSA. In conclusion, plasma XOR redox is closely related to HSA redox, particularly reversible oxidation of HSA.