Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart
Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart
复制标题
DOI：
10.1016/j.yjmcc.2015.01.004
复制
发表时间：
2015-03-01
影响因子：
5
通讯作者：
Miura, Tetsuji
中科院分区：
文献类型：
--
作者：
Kouzu, Hidemichi;Miki, Takayuki;Miura, Tetsuji
2型糖尿病（T2DM）常并发舒张性心力衰竭，在负荷增加后失代偿。以心脏代谢组学为重点，我们研究了T2DM在压力过载时增加心室舒张刚度的机制。在T2DM OLETF模型和非糖尿病对照组LETO模型中，在基线和通过输注苯肾上腺素升高主动脉压期间测定压力-容积关系（PVRs）和心肌代谢组。压力过载增强了OLETF患者的舒张刚度，但没有改变收缩储备，这可以通过舒张末期PVR向左向上移动来显示。相比之下，缓冲灌注离体心脏在OLETF和LETO中心脏骤停时的PVRs相似，表明细胞外基质或titin重塑并不是OLETF后负荷诱导的跳动心室刚度增加的原因。代谢组学分析显示OLETF的糖酵解和戊糖磷酸途径的促进作用受损。压力过载显著降低了OLETF的34%和40%的ATP和总腺嘌呤核苷酸，而LETO没有，而nadh与nad（+）比值在两组中相似。OLETF中压力过载导致的ATP下降与肌苷5-单磷酸增加和腺苷水平下降有关，这与OLETF中心脏AMP脱氨酶活性升高2.5倍相一致。组织ATP水平与左室压tau、LVEDP呈负相关。这些结果表明，在2型糖尿病心脏急性压力超载期间，AMP脱氨酶对腺嘌呤核苷酸的过度降解导致ATP耗竭是导致心室硬化的根本原因。(C) 2015 Elsevier Ltd.版权所有。
Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure-volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD(+) ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts. (C) 2015 Elsevier Ltd. All rights reserved.