Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 154, Issue -, Pages 21-31Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2021.01.002
Keywords
AMP deaminase; Xanthine oxidoreductase; Diabetic cardiomyopathy; Heart failure; Mitochondria
Categories
Funding
- Japan Society for the Promotion of Science, Tokyo, Japan [17 K09584]
- Sanwa Kagaku Kenkyusho, Co. Ltd., Mie, Japan
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The study revealed that there is a functional connection between upregulated AMP deaminase (AMPD) and xanthine oxidoreductase (XOR) in diabetic rat hearts, leading to aggravated ventricular dysfunction. The findings suggest that increased XOR activity and formation of XOR substrates by AMPD contribute to abnormal cardiac function through ROS mediation under conditions of hypertension-induced pressure overload.
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.
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