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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Hypertrophic cardiomyopathy and dysregulation of cardiac energetics in a mouse model of biliary fibrosis.
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Hypertrophic cardiomyopathy and dysregulation of cardiac energetics in a mouse model of biliary fibrosis.

机译：肥厚型心肌病和胆汁纤维化小鼠模型中心脏能量的异常调节。

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Cardiac dysfunction is a major cause of morbidity and mortality in patients with end-stage liver disease; yet the mechanisms remain largely unknown. We hypothesized that the complex interrelated impairments in cardiac structure and function secondary to progression of liver diseases involve alterations in signaling pathways engaged in cardiac energy metabolism and hypertrophy, augmented by direct effects of high circulating levels of bile acids. Biliary fibrosis was induced in male C57BL/6J mice by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) supplemented diet. After 3 weeks, mice underwent live imaging (dual energy x-ray absorptiometry [DEXA] scanning, two-dimensional echocardiography [2DE], electrocardiography, cardiac magnetic resonance imaging), exercise treadmill testing, and histological and biochemical analyses of livers and hearts. Compared with chow-fed mice, DDC-fed mice fatigued earlier on the treadmill, with reduced VO(2). Marked changes were identified electrophysiologically (bradycardia and prolonged QT interval) and functionally (hyperdynamic left ventricular [LV] contractility along with increased LV thickness). Hearts of DDC-fed mice showed hypertrophic signaling (activation of v-akt murine thymoma viral oncogene/protein kinase B [AKT], inhibition of glycogen synthase kinase-3beta [GSK3beta], a 20-fold up-regulation of beta myosin heavy chain RNA and elevated G(s)alpha/G(i)alpha ratio. Genes regulating cardiac fatty acid oxidation pathways were suppressed, along with a threefold increase in myocardial glycogen content. Treatment of mouse cardiomyocytes (which express the membrane bile acid receptor TGR5) with potent natural TGR5 agonists, taurochenodeoxycholic acid and lithocholic acid, activated AKT and inhibited GSK3beta, similar to the changes seen in DDC-fed mouse hearts. This provides support for a novel mechanism whereby circulating natural bile acids can induce signaling pathways in heart associated with hypertrophy. CONCLUSION: Three weeks of DDC feeding-induced biliary fibrosis leads to multiple functional, metabolic, electrophysiological, and hypertrophic adaptations in the mouse heart, recapitulating some of the features of human cirrhotic cardiomyopathy.
机译：心脏功能障碍是终末期肝病患者发病和死亡的主要原因。然而，机制仍然未知。我们假设肝脏疾病进展继发于心脏结构和功能的复杂的相互关联的损伤涉及参与心脏能量代谢和肥大的信号传导途径的改变，高循环水平的胆汁酸的直接作用加剧了这一过程。通过补充0.1％3,5-二乙氧基羰基-1,4-二羟基可乐定（DDC）的饮食，在雄性C57BL / 6J小鼠中诱发胆汁纤维化。 3周后，对小鼠进行实时成像（双能X射线吸收测定[DEXA]扫描，二维超声心动图[2DE]，心电图，心脏磁共振成像），运动跑步机测试以及肝脏和心脏的组织学和生化分析。与食物喂养的老鼠相比，DDC喂养的老鼠在跑步机上较早疲劳，VO（2）降低。可以通过电生理学（心动过缓和延长的QT间隔）和功能（高动力性左心室[LV]收缩性以及LV厚度增加）识别出明显的变化。用DDC喂养的小鼠的心脏显示出肥大信号（激活v-akt鼠胸腺瘤病毒癌基因/蛋白激酶B [AKT]，抑制糖原合酶激酶3beta [GSK3beta]，β肌球蛋白重链上调20倍RNA和G（s）alpha / G（i）alpha比例升高;调节心脏脂肪酸氧化途径的基因被抑制，心肌糖原含量增加三倍;治疗小鼠心肌细胞（表达膜胆汁酸受体TGR5）与强效天然TGR5激动剂，牛磺去氧胆酸和石胆酸，活化的AKT和抑制的GSK3beta相似，类似于在DDC喂养的小鼠心脏中所见的变化，这为循环中的天然胆汁酸可以诱导与之相关的心脏中的信号传导途径提供了新机制。结论：DDC喂养引起的胆汁纤维化三周导致小鼠的多种功能，代谢，电生理和肥大适应艺术，概括了人类肝硬化性心肌病的某些特征。

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