Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction.
Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction.
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DOI：
10.1016/j.yjmcc.2010.10.023
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发表时间：
2011-01
影响因子：
5
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Ceylan-Isik AF;Sreejayan N;Ren J
ER应激参与了肥胖的病理生理过程，但对ER应激在肥胖相关心功能不全中的作用知之甚少。本研究旨在探讨ER伴侣牛磺熊去氧胆酸（TUDCA）对肥胖诱导的心肌功能障碍的影响。成年瘦小鼠和ob/ob肥胖小鼠用TUDCA（50 mg/kg/d，p.o.）进行口服葡萄糖耐量试验（OGTT）。超声心动图，心肌细胞收缩和细胞内钙离子特性进行了评估。采用~（45）Ca ~（2+）摄取法测定肌浆网Ca ~（2+）-ATP酶（SERCA）活性，Western blot法测定细胞内Ca ~（2+）调节蛋白的表达。胰岛素信号，ER应激标志物和HSP 90进行了评估。我们的研究结果表明，长期TUDCA治疗降低了肥胖小鼠的收缩压和葡萄糖耐受不良。肥胖导致舒张期内径增加、心脏肥大、缩短率受损、心肌细胞收缩性（峰值缩短、最大缩短/再舒张速度和收缩/舒张持续时间）和细胞内Ca 2+特性，所有这些均被TUDCA显著减弱。TUDCA调和了肥胖相关的SERCA活性和表达降低，以及IRS丝氨酸磷酸化、总cJun和磷酸化cJun、ER应激标志物Bip、peIF 2 α和pPERK的增加。肥胖诱导的受磷蛋白和HSP 90的变化不受TUDCA的影响。体外实验结果显示，TUDCA消除棕榈酸诱导的心肌细胞收缩功能障碍。总之，这些数据描述了ER应激在肥胖相关的心脏收缩功能障碍中的关键作用，表明ER应激作为肥胖心脏功能障碍管理的靶点的治疗潜力。
ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated TUDCA (50 mg/kg/d, p.o.) or vehicle for 5 wks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca2+ properties were assessed. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity and protein expression of intracellular Ca2+ regulatory proteins were measured using 45Ca2+ uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lower systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca2+ properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decreased in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity.
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影响因子：
20.1
作者：
Flagg, Thomas P.;Cazorla, Olivier;Nerbonne, Jeanne M.
通讯作者：
Nerbonne, Jeanne M.
牛磺酸熊去氧胆酸对培养小鼠足细胞内质网应激和晚期糖基化终产物诱导的细胞凋亡的影响
影响因子：
4.2
作者：
Chen, Yu;Liu, Cui Ping;Liu, Chao
通讯作者：
Liu, Chao
影响因子：
37.8
作者：
Adachi, T;Matsui, R;Cohen, RA
通讯作者：
Cohen, RA
影响因子：
8.2
作者：
Li, SY;Yang, X;Ren, J
通讯作者：
Ren, J
DOI：
10.1111/j.1440-1681.2006.04331.x
发表时间：
2006-01-01
影响因子：
2.9
作者：
Ceylan-Isik, AF;LaCour, KH;Ren, J
通讯作者：
Ren, J