Hypertrophic Cardiomyopathy and Dysregulation of Cardiac Energetics in a Mouse Model of Biliary Fibrosis
Hypertrophic Cardiomyopathy and Dysregulation of Cardiac Energetics in a Mouse Model of Biliary Fibrosis
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DOI：
10.1002/hep.23585
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发表时间：
2010-06-01
期刊：
影响因子：
13.5
通讯作者：
Karpen, Saul J.
中科院分区：
文献类型：
--
作者：
Desai, Moreshwar S.;Shabier, Zainuer;Karpen, Saul J.
心功能不全是终末期肝病患者发病率和死亡率的主要原因；然而，其机制在很大程度上仍不清楚。我们假设，继发于肝病进展的复杂的相互关联的心脏结构和功能损害涉及参与心脏能量代谢和肥大的信号通路的改变，并因高循环胆汁酸水平的直接影响而加剧。以添加0.1%3，5-二乙氧基甲酰-1，4-二羟基胆碱(DDC)的饲料诱导雄性C57BL/6J小鼠胆汁纤维化。3周后，小鼠接受活体成像(双能X射线吸收法[DEKA]扫描、二维超声心动图[2DE]、心电图学、心脏磁共振成像)、运动跑台试验以及肝脏和心脏的组织学和生化分析。与喂食食物的小鼠相比，喂食DDC的小鼠在跑步机上疲劳的时间更早，VO2减少。在电生理方面(心动过缓和QT间期延长)和功能上(随着左心室厚度的增加而高度动力的左心室收缩能力)发生了显著的变化。饲喂DDC的小鼠心脏出现肥大信号(v-AKT激活小鼠胸腺瘤病毒癌基因/蛋白激酶B[AKT]，抑制糖原合酶激酶-3β[GSIC3β]，β肌球蛋白重链RNA上调20倍，G(S)α/G(I)α比值升高。调控心脏脂肪酸氧化途径的基因被抑制，同时心肌糖原含量增加了三倍。用强大的天然TGR5激动剂牛磺鹅去氧胆酸和石胆酸处理小鼠心肌细胞(表达膜胆汁酸受体TGR5)，激活AKT并抑制GSK3β，与DDC喂养的小鼠心脏的变化相似。这为一种新的机制提供了支持，即循环中的天然胆汁酸可以在心脏中诱导与肥厚相关的信号通路。结论：三周DDC喂养诱导的胆汁纤维化导致小鼠心脏多种功能、代谢、电生理和肥大适应，概括了人类肝硬化性心肌病的一些特征。(《肝病》2010；51：2097-2107)
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 [DEKA] 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 VO2. 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-3 beta [GSIC3 beta], 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 GSK3 beta, 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. (HEPATOLOGY 2010;51:2097-2107)