β-Adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines
β-Adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines
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DOI：
10.1093/cvr/cvr106
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发表时间：
2011-08-01
影响因子：
10.8
通讯作者：
Wang, Jie
中科院分区：
文献类型：
--
作者：
George, Isaac;Sabbah, Hani N.;Wang, Jie
目的 内质网/肌浆网 (ER) 中钙稳态的改变会导致 ER 应激，最终可能影响心室功能。然而，尚未研究 ER 应激在 β 受体阻滞剂治疗充血性心力衰竭 (CHF) 中的作用。本研究检查了 CHF 中的 ER 应激，并评估了其在缺血性 CHF 犬模型中 β 受体阻滞剂治疗中的作用。方法和结果 CHF 是通过对长期接受仪器治疗的狗进行每日冠状动脉栓塞而产生的。口服β受体阻滞剂美托洛尔或载体12周后，通过蛋白质印迹分析评估Ca2+转运蛋白，包括肌浆网Ca2+-ATP酶（SERCA）、兰尼碱受体（RyR2）、Na+-Ca2+交换器（NCX1）、Ca2+储存蛋白钙网蛋白（CRT）和受磷蛋白。还检查了 ER 应激标记物磷酸化真核起始因子 2 α (eIF2 α-P) 的细胞水平。与媒介物治疗组相比，美托洛尔显着改善心脏功能，恢复 SERCA2a、NCX1 和 CRT 蛋白，增加磷酸化受磷蛋白，逆转蛋白激酶 A RyR2 过度磷酸化，导致 ER 应激标志物 eIF2a-P 正常化并减少 DNA 损伤。 CHF 中的 Ca2+ 稳态。钙处理蛋白功能的恢复以及由此导致的内质网应激的减少可能部分解释了在慢性心力衰竭中观察到的β-阻断剂的有益作用。这种机制是否发生在其他动物 CHF 模型或人类 CHF 模型中值得进一步研究。
Aims Alterations in calcium homeostasis in the endoplasmic/sarcoplasmic reticulum (ER) cause ER stress that ultimately may affect ventricular function. However, the role of ER stress in beta-blocker therapy for congestive heart failure (CHF) has not been studied. This study examined ER stress in CHF and evaluated its role in b-blocker therapy in a canine model of ischaemic CHF.Methods and results CHF was created by daily coronary embolization in chronically instrumented dogs. After oral administration of beta-blocker metoprolol or vehicle for 12 weeks, Ca2+ transport proteins including sarcoplasmic reticulum Ca2+-ATPase (SERCA), ryanodine receptor (RyR2), Na+-Ca2+ exchanger (NCX1), Ca2+ storage protein calreticulin (CRT), and phospholamban were evaluated by Western blot analysis. Cellular levels of ER stress marker, phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha-P), were also examined. Compared with the vehicle-treated group, metoprolol caused significantly improved cardiac function, restored the proteins of SERCA2a, NCX1, and CRT, increased phosphorylated phospholamban, reversed protein kinase A hyperphosphorylation of RyR2, and resulted in normalized ER stress marker eIF2a-P and reduced DNA damage.Conclusions Our results suggest that ER stress could be induced by abnormal Ca2+ homeostasis in CHF. The restoration of calcium-handling protein function and resultant decrease in ER stress might, in part, explain the beneficial effects of beta-blockade observed in CHF. Whether this mechanism occurs in other animal CHF models or human CHF warrants further study.