Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Cardiovasc Res. 2011 Aug 1;91(3):447-55. doi: 10.1093/cvr/cvr106. Epub 2011 Apr 14.
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 β-blocker therapy for congestive heart failure (CHF) has not been studied. This study examined ER stress in CHF and evaluated its role in β-blocker therapy in a canine model of ischaemic CHF.
CHF was created by daily coronary embolization in chronically instrumented dogs. After oral administration of β-blocker metoprolol or vehicle for 12 weeks, Ca(2+) transport proteins including sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), ryanodine receptor (RyR2), Na(+)-Ca(2+) exchanger (NCX1), Ca(2+) storage protein calreticulin (CRT), and phospholamban were evaluated by Western blot analysis. Cellular levels of ER stress marker, phosphorylated eukaryotic initiation factor 2α (eIF2α-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 eIF2α-P and reduced DNA damage.
Our results suggest that ER stress could be induced by abnormal Ca(2+) homeostasis in CHF. The restoration of calcium-handling protein function and resultant decrease in ER stress might, in part, explain the beneficial effects of β-blockade observed in CHF. Whether this mechanism occurs in other animal CHF models or human CHF warrants further study.
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，ER 应激在β受体阻滞剂治疗充血性心力衰竭（CHF）中的作用尚未得到研究。本研究检测了 CHF 中的 ER 应激，并在缺血性 CHF 的犬模型中评估了其在β受体阻滞剂治疗中的作用。
通过在慢性仪器化犬中每日冠状动脉栓塞来创建 CHF。在口服β受体阻滞剂美托洛尔或载体 12 周后，通过 Western blot 分析评估 Ca(2+)转运蛋白，包括肌浆网 Ca(2+) -ATP 酶（SERCA）、ryanodine 受体（RyR2）、Na(+) -Ca(2+)交换体（NCX1）、Ca(2+)储存蛋白钙网织蛋白（CRT）和磷蛋白。还检查了 ER 应激标志物磷酸化真核起始因子 2α（eIF2α-P）的细胞水平。与载体处理组相比，美托洛尔显著改善了心脏功能，恢复了 SERCA2a、NCX1 和 CRT 的蛋白，增加了磷酸化磷蛋白，逆转了 RyR2 蛋白激酶 A 的过度磷酸化，并使 ER 应激标志物 eIF2α-P 正常化和减少 DNA 损伤。
我们的结果表明，ER 应激可能是由 CHF 中异常的 Ca(2+)稳态引起的。钙处理蛋白功能的恢复和由此产生的 ER 应激的减少可能部分解释了在 CHF 中观察到的β受体阻滞剂的有益作用。这种机制是否发生在其他动物 CHF 模型或人类 CHF 中，需要进一步研究。
