Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload
Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload
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DOI：
10.1016/j.yjmcc.2021.01.002
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发表时间：
2021-02-09
影响因子：
5
通讯作者：
Miura, Tetsuji
中科院分区：
文献类型：
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作者：
Igaki, Yusuke;Tanno, Masaya;Miura, Tetsuji
背景：我们先前报道，上调的AMP脱氨酶(AMPD)通过耗尽2型糖尿病(T2 DM)大鼠模型-大冢Long-Evans-Tokushima Fatty大鼠(OLETF)的腺嘌呤核苷酸池而导致舒张期心功能不全。同时，AMPD促进黄嘌呤氧化还原酶(XOR)底物的形成，XOR作为副产物产生ROS。方法和结果：压力-容量环路分析显示，与LETO非糖尿病大鼠相比，OLETF组大鼠压力超负荷导致更严重的左室舒张功能障碍(tau：14.7±0.8vs 12.5±0.7ms，左室舒张末期压：18.3±1.5vs 12.2±1.3 mm Hg，p<；0.05)。压力超负荷不影响AMPD活性，但使OLETF和LETO的XOR活性增加，其中OLETF的XOR活性显著高于LETO(347.2±17.9vs243.2±6.1g/m in/mg)。在压力超负荷条件下，OLETF组心肌ATP水平低于LETO组，黄嘌呤和尿酸水平高于LETO组。在心脏匀浆中加入外源性肌苷(AMP脱氨的产物)可增强XOR活性。与LETO相比，OLETF的组织ROS水平增加了68%，线粒体状态3呼吸减少了47%。在H9c2细胞中过表达AMPD3可增加次黄嘌呤和ROS的水平，降低ATP的水平。在压力超负荷状态下，抑制XOR可抑制OLETF组织ROS的产生和线粒体功能障碍，改善心功能。结论：在糖尿病心脏心脏负荷增加时，XOR活性增加和AMPD上调XOR底物形成XOR底物参与了ROS介导的舒张性心功能障碍。
Background: We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats.Methods and results: Pressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ? 0.8 vs 12.5 ? 0.7 msec, left ventricular enddiastolic pressure: 18.3 ? 1.5 vs 12.2 ? 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ? 17.9 vs 243.2 ? 6.1 ?g/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF.Conclusions: The results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.