Luo Tao, Chen Baihe, Wang Xianbao
Division of Cardiology, Department of Medicine, University of California Irvine Medical Center, Orange, CA 92868, USA.
Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
Chem Biol Interact. 2015 Dec 5;242:99-106. doi: 10.1016/j.cbi.2015.09.025. Epub 2015 Sep 30.
Our previous study indicated that attenuation of endoplasmic reticulum (ER) stress by administration of 4-phenylbutyric acid (4-PBA) could prevent cardiac rupture and remodeling in a mouse model of myocardial infarction (MI). However, whether 4-PBA is protective in hypertrophic heart disease is unclear. Thus, we tested the therapeutic effect of 4-PBA on pressure-overload induced myocardial hypertrophy. Transverse aortic constriction (TAC) was used to create myocardial hypertrophy in C57BL/6 male mice for 4 weeks. Immediately after surgery, the mice were administrated either 4-PBA (20 mg/kg/day) or 0.9% NaCl by intraperitoneal injection. At the end of 4 weeks, the mice underwent high-resolution echocardiographic imaging. Our results showed that both the left ventricular posterior wall thickness at end systole (LVPWs) and diastole (LVPWd) were increased in the TAC group, compared to control. 4-PBA administration attenuated hypertrophy and decreased the heart weight over body weight ratio. Masson's trichrome staining showed that myocardial interstitial fibrosis and collagen deposition were also decreased by 4-PBA. We next detected the ER stress response in the heart tissues of TAC mice in different time points. Western blotting showed that the expression of ER stress marker, GRP78, CHOP and phosphor-PERK, were persistently increased 4 weeks after TAC. The treatment of 4-PBA inhibited the expression of ER stress markers. We also demonstrated that the 4-PBA at 20 mg/kg/day had no effect on histone 3 deacetylation inhibition, while attenuating ER stress and TAC-induced hypertrophy. These findings suggest that 4-PBA may be a therapeutic strategy to consider in preventing pressure-overload induced myocardial hypertrophy and interstitial fibrosis by selectively attenuating ER stress.
我们之前的研究表明，通过给予4-苯基丁酸（4-PBA）减轻内质网（ER）应激，可以预防心肌梗死（MI）小鼠模型中的心脏破裂和重塑。然而，4-PBA在肥厚性心脏病中是否具有保护作用尚不清楚。因此，我们测试了4-PBA对压力超负荷诱导的心肌肥大的治疗效果。采用横向主动脉缩窄（TAC）法在C57BL/6雄性小鼠中诱导心肌肥大4周。手术后立即通过腹腔注射给予小鼠4-PBA（20 mg/kg/天）或0.9%氯化钠。在4周结束时，对小鼠进行高分辨率超声心动图成像。我们的结果显示，与对照组相比，TAC组的收缩末期左心室后壁厚度（LVPWs）和舒张末期左心室后壁厚度（LVPWd）均增加。给予4-PBA可减轻肥大并降低心脏重量与体重之比。Masson三色染色显示，4-PBA还可减少心肌间质纤维化和胶原沉积。接下来，我们在不同时间点检测了TAC小鼠心脏组织中的ER应激反应。蛋白质印迹法显示，TAC后4周，ER应激标志物GRP78、CHOP和磷酸化PERK的表达持续增加。4-PBA治疗可抑制ER应激标志物的表达。我们还证明，20 mg/kg/天的4-PBA对组蛋白3去乙酰化抑制没有影响，但可减轻ER应激和TAC诱导的肥大。这些发现表明，4-PBA可能是一种值得考虑的治疗策略，通过选择性减轻ER应激来预防压力超负荷诱导的心肌肥大和间质纤维化。
