Association of Plasma Xanthine Oxidoreductase with Arterial Stiffness in Type 2 Diabetes with Liver Dysfunction

Ohira, Masahiro; Tanaka, Shou; Watanabe, Yasuhiro; Nakamura, Shoko; Oka, Rena; Yamaguchi, Takashi; Ban, Noriko; Saiki, Atsuhito; Ishihara, Noriko; Murano, Takeyoshi; Murase, Takayo; Nakamura, Takashi; Tatsuno, Ichiro

doi:10.1016/j.amjms.2021.09.011

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…Moreover, high XOR in liver disease conditions accelerated purine catabolism in the plasma per se using hypoxanthine secreted from vascular endothelial cells or adipocytes as substrate, which was accompanied by the development of vascular endothelial injury and neointimal proliferation [ 11 , 12 , 13 ]. Additionally, a cross-sectional study by another group reported a significant positive correlation between plasma XOR activity and CAVI in patients with type 2 diabetes and liver dysfunction [ 30 ]. These results suggest pathological crosstalk from the damaged liver to vascular diseases via hepatic XOR.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

et al. 2023

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Background: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. Methods: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. Results: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. Conclusions: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

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Section: Discussionmentioning

confidence: 99%

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

et al. 2023

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“…Studies of liver function in diabetic organisms showed that 28.0 to 36.8% of patients had liver dysfunction ( 41 , 42 ). Prolonged fatty infiltration of the liver in the diabetic has been shown to lead to hepatic cirrhosis ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Linking Mitochondrial Function to Insulin Resistance: Focusing on Comparing the Old and the Young

Wang

et al. 2022

Front. Nutr.

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Long-term intake of high-energy diet can lead to decreased insulin sensitivity and even insulin resistance, eventually leading to diabetes. Diabetes often occurs in middle-aged and elderly people. However, there is growing evidence that the incidence rate of young body is increasing over the years. This means that insulin resistance can be caused by excessive energy intake in both young and old people. In this study, high-fat diet (HFD) and normal diet were fed to rats of elderly experimental group (EE), elderly control group (EC), young experimental group (YE), and young control group (YC), respectively, for 8 weeks, by which insulin resistance model was obtained. Insulin sensitivity was measured, histopathology changes in liver and skeletal muscle tissues were observed, and mitochondrial fusion and division and cell senescence were detected in four groups of rats. The results showed that both young and elderly rats developed significant insulin resistance, fat deposition, decline of mitochondrial function and mitochondrial biosynthesis in liver and skeletal muscle, and cell aging after HFD feeding. In addition, the degree of mitochondrial dysfunction and aging in young rats was similar to that of aged rats fed a normal diet after HFD. This experiment provides a reference for an in-depth study of the regulatory mechanisms of cellular energy metabolism in this state.

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“…Arterial stiffness is generally recognized as a predictor of cardiovascular morbidity and mortality, and its increase reflects the remodeling of arterial structures caused by the proliferation of SMCs and connective tissue in the diffuse medial layer of the vessel wall [125,126]. A previous cross-sectional study reported a significant positive correlation between plasma XOR activity and CAVI in patients with type 2 diabetes and liver dysfunction [127]. In addition, we have recently reported that arterial stiffness parameters (CAVI and brachialankle pulse wave velocity, baPWV) were significantly improved after 24 weeks of treatment with topiroxostat in hyperuricemic hypertensive patients with higher baseline ALT levels, which was accompanied by suppression of elevated plasma XOR activity [128].…”

Section: Increased Circulating Xor Activity In Nafld Conditions and I...mentioning

confidence: 99%

Cardiovascular significance of adipose-derived adiponectin and liver-derived xanthine oxidoreductase in metabolic syndrome

et al. 2023

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Visceral fat-based metabolic syndrome has a strong impact on atherosclerotic cardiovascular disease (CVD), clustering diabetes, dyslipidemia, hypertension, hyperuricemia, and non-alcoholic fatty liver disease (NAFLD). Adiponectin, a protein specifically secreted by adipocytes, circulates abundantly in the human bloodstream, but its concentration decreases under pathological conditions such as visceral fat accumulation. Extensive clinical evidence has demonstrated that hypoadiponectinemia is associated with the development of CVD and chronic organ diseases. Although several binding partners of adiponectin, such as AdipoR1/2, have been identified, how adiponectin exerts its multiple beneficial effects on various organs remains to be fully elucidated. Recent progress in adiponectin research has revealed that adiponectin accumulates on cardiovascular tissues by binding to a unique glycosylphosphatidylinositol-anchored T-cadherin. The adiponectin/T-cadherin complex enhances exosome biogenesis and secretion, which may contribute to the maintenance of cellular homeostasis and tissue regeneration, particularly in the vasculature. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catabolizes hypoxanthine and xanthine to uric acid. XOR produces reactive oxygen species in the reaction process, suggesting that XOR is involved in the pathological mechanism underlying CVD progression. Recent findings from clinical and laboratory studies have shown strong positive correlations between plasma XOR activity and liver enzymes. Furthermore, especially in NAFLD conditions, excessive hepatic XOR leaked into the bloodstream accelerates purine catabolism in the circulation, using hypoxanthine secreted from vascular endothelial cells and adipocytes, which can promote vascular remodeling. In this review, we focused on the cardiovascular significance of adipose-derived adiponectin and liverderived XOR in the development of CVD associated with metabolic syndrome.

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Association of Plasma Xanthine Oxidoreductase with Arterial Stiffness in Type 2 Diabetes with Liver Dysfunction

Cited by 3 publications

References 35 publications

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

Linking Mitochondrial Function to Insulin Resistance: Focusing on Comparing the Old and the Young

Cardiovascular significance of adipose-derived adiponectin and liver-derived xanthine oxidoreductase in metabolic syndrome

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