嘧啶核苷尿苷及其磷酸化衍生物已被证明参与能量和氧化还原平衡的系统调节,并促进许多组织的再生。包括心肌,尽管潜在的机制还没有完全理解。此外,心肌细胞内线粒体结构和功能的重排是心肌损伤的主要标志。因此,本研究旨在探讨尿苷是否能减轻异丙肾上腺素(ISO)暴露所致的急性心肌损伤,应激性心肌病大鼠模型,并阐明其与线粒体功能障碍相关的作用机制。为此,我们结合透射电子显微镜和心脏线粒体功能的综合研究,对相关血清生物标志物进行了生化分析和心电图监测.ISO(150mg/kg,两次,间隔24小时,s.c.)对大鼠引起的心肌退行性变化,血清心脏特异性标志物肌钙蛋白I和AST/ALT比值急剧增加,左心室心肌ATP水平下降。并行,肌节组织的改变与肌原纤维的局灶性解体,线粒体的超微结构和形态缺陷,包括crista膜的取向和堆积密度的干扰,被检测到。这些故障通过尿苷(30mg/kg,两次,间隔24小时,i.p.)。尿苷还导致QT间隔的正常化。此外,尿苷有效抑制ISO诱导的大鼠心脏线粒体ROS过度产生和脂质过氧化。服用尿苷部分恢复了呼吸链复合物V的蛋白质水平,随着ATP合成和线粒体钾转运的速率,表明通过mitoKATP通道激活钾循环。一起来看,这些结果表明,尿苷可以改善ISO诱导的急性心肌损伤和线粒体功能障碍,这可能是由于线粒体钾循环的激活和轻度解偶联导致ROS产生减少和氧化损伤。
The pyrimidine nucleoside uridine and its phosphorylated derivates have been shown to be involved in the systemic regulation of energy and redox balance and promote the regeneration of many tissues, including the myocardium, although the underlying mechanisms are not fully understood. Moreover, rearrangements in mitochondrial structure and function within cardiomyocytes are the predominant signs of myocardial injury. Accordingly, this study aimed to investigate whether uridine could alleviate acute myocardial injury induced by isoprenaline (ISO) exposure, a rat model of stress-induced cardiomyopathy, and to elucidate the mechanisms of its action related to mitochondrial dysfunction. For this purpose, a biochemical analysis of the relevant serum biomarkers and ECG monitoring were performed in combination with transmission electron microscopy and a comprehensive study of cardiac mitochondrial functions. The administration of ISO (150 mg/kg, twice with an interval of 24 h, s.c.) to rats caused myocardial degenerative changes, a sharp increase in the serum cardiospecific markers troponin I and the AST/ALT ratio, and a decline in the ATP level in the left ventricular myocardium. In parallel, alterations in the organization of sarcomeres with focal disorganization of myofibrils, and ultrastructural and morphological defects in mitochondria, including disturbances in the orientation and packing density of crista membranes, were detected. These malfunctions were improved by pretreatment with uridine (30 mg/kg, twice with an interval of 24 h, i.p.). Uridine also led to the normalization of the QT interval. Moreover, uridine effectively inhibited ISO-induced ROS overproduction and lipid peroxidation in rat heart mitochondria. The administration of uridine partially recovered the protein level of the respiratory chain complex V, along with the rates of ATP synthesis and mitochondrial potassium transport, suggesting the activation of the potassium cycle through the mitoKATP channel. Taken together, these results indicate that uridine ameliorates acute ISO-induced myocardial injury and mitochondrial malfunction, which may be due to the activation of mitochondrial potassium recycling and a mild uncoupling leading to decreased ROS generation and oxidative damage.