Abstract

Diabetes mellitus is one of the major causes of ischemic and nonischemic heart failure. While hypertension and coronary artery disease are frequent comorbidities in patients with diabetes, cardiac contractile dysfunction and remodeling occur in diabetic patients even without comorbidities, which is referred to as diabetic cardiomyopathy. Investigations in recent decades have demonstrated that the production of reactive oxygen species (ROS), impaired handling of intracellular Ca²⁺, and alterations in energy metabolism are involved in the development of diabetic cardiomyopathy. AMP deaminase (AMPD) directly regulates adenine nucleotide metabolism and energy transfer by adenylate kinase and indirectly modulates xanthine oxidoreductase-mediated pathways and AMP-activated protein kinase-mediated signaling. Upregulation of AMPD in diabetic hearts was first reported more than 30 years ago, and subsequent studies showed similar upregulation in the liver and skeletal muscle. Evidence for the roles of AMPD in diabetes-induced fatty liver, sarcopenia, and heart failure has been accumulating. A series of our recent studies showed that AMPD localizes in the mitochondria-associated endoplasmic reticulum membrane as well as the sarcoplasmic reticulum and cytosol and participates in the regulation of mitochondrial Ca²⁺ and suggested that upregulated AMPD contributes to contractile dysfunction in diabetic cardiomyopathy via increased generation of ROS, adenine nucleotide depletion, and impaired mitochondrial respiration. The detrimental effects of AMPD were manifested at times of increased cardiac workload by pressure loading. In this review, we briefly summarize the expression and functions of AMPD in the heart and discuss the roles of AMPD in diabetic cardiomyopathy, mainly focusing on contractile dysfunction caused by this disorder.

中文翻译：

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AMP 脱氨酶在糖尿病心肌病中的作用

摘要

糖尿病是缺血性和非缺血性心力衰竭的主要原因之一。虽然高血压和冠状动脉疾病是糖尿病患者常见的合并症，但即使没有合并症，糖尿病患者也会出现心脏收缩功能障碍和重构，这被称为糖尿病心肌病。近几十年的研究表明，活性氧（ROS）的产生、细胞内Ca ²⁺的处理受损以及能量代谢的改变与糖尿病心肌病的发展有关。AMP 脱氨酶 (AMPD) 通过腺苷酸激酶直接调节腺嘌呤核苷酸代谢和能量转移，并间接调节黄嘌呤氧化还原酶介导的途径和 AMP 激活的蛋白激酶介导的信号传导。30 多年前首次报道了糖尿病心脏中 AMPD 的上调，随后的研究表明肝脏和骨骼肌中也有类似的上调。关于 AMPD 在糖尿病引起的脂肪肝、肌肉减少症和心力衰竭中的作用的证据不断积累。我们最近的一系列研究表明，AMPD 定位于线粒体相关的内质网膜以及肌浆网和细胞质，并参与线粒体 Ca ²⁺的调节，并表明上调的 AMPD 通过增加ROS 的产生、腺嘌呤核苷酸消耗和线粒体呼吸受损。AMPD 的有害影响在压力负荷增加心脏工作负荷时表现出来。本文简要总结了 AMPD 在心脏中的表达和功能，并讨论了 AMPD 在糖尿病心肌病中的作用，重点讨论了该疾病引起的收缩功能障碍。