β-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure
β-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure
复制标题
DOI：
10.1161/01.cir.0000068316.53218.49
复制
发表时间：
2003-05-20
期刊：
影响因子：
37.8
通讯作者：
Marks, AR
中科院分区：
文献类型：
--
作者：
Reiken, S;Wehrens, XHT;Marks, AR
背景-慢性β-肾上腺素能受体(β-AR)阻断可改善心力衰竭患者的心脏收缩能力，延长患者的生存时间；然而，这些有利反应的机制尚不清楚。应激诱导的交感神经系统激活导致蛋白激酶A(PKA)介导的钙释放通道/心脏兰尼定受体(RyR2)的磷酸化，这是心脏兴奋-收缩(EC)偶联所必需的，激活RyR2通道，增加心肌收缩能力。心力衰竭的高肾上腺素状态导致RyR2通道泄漏，可归因于PKA过度磷酸化和稳定的FK506结合蛋白FKBP12.6的耗尽。我们测试了这一假说，即在心力衰竭患者中，由于β-AR阻断而改善的心肌功能与恢复正常的RyR2通道功能有关。方法和结果--我们使用来自移植患者的肌条来评估β-AR阻断对左心室容量的影响以及使用β-受体激动剂的反应性。检查了24个人的心脏，10个来自接受β-AR阻滞剂(卡维地洛、美托洛尔或阿替洛尔)治疗的心力衰竭患者，9个来自没有接受β-AR阻滞剂治疗的心力衰竭患者，5个正常心脏。RyR2大分子复合体中的FKBP12.6用免疫共沉淀法测定，RyR2大分子复合体中的FKBP12.6用平面脂双层测定通道功能。β-AR阻滞剂减少了心力衰竭患者的左心室容量(反向重塑)，并恢复了心肌中的β-激动剂反应。心肌功能的改善与RyR2大分子复合体中正常FKBP12.6水平的恢复和RyR2通道功能的恢复有关。结论：心力衰竭患者在β-AR阻断期间心肌功能的改善与心肌钙释放通道功能的改善有关。
Background-Chronic beta-adrenergic receptor (beta-AR) blockade improves cardiac contractility and prolongs survival in patients with heart failure; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the calcium (Ca2+) release channel/cardiac ryanodine receptor (RyR2), required for cardiac excitation-contraction (EC) coupling, activating the RyR2 channel, and increasing cardiac contractility. The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. We tested the hypothesis that improved cardiac muscle function attributable to beta-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure.Methods and Results-We assessed the effects of beta-AR blockade on left ventricular volume using isolated perfused hearts and beta-agonist responsiveness using muscle strips from patients undergoing transplantation. Twenty-four human hearts were examined, 10 from patients with heart failure treated with beta-AR blockers (carvedilol, metoprolol, or atenolol), 9 from patients with heart failure without beta-AR blocker treatment, and 5 normal hearts. RyR2 PKA phosphorylation was determined by back-phosphorylation, FKBP12.6 in the RyR2 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. beta-AR blockers reduced left ventricular volume (reverse remodeling) and restored beta-agonist response in cardiac muscle from patients with heart failure. Improved cardiac muscle function was associated with restoration of normal FKBP12.6 levels in the RyR2 macromolecular complex and RyR2 channel function.Conclusions-Improved cardiac muscle function during beta-AR blockade is associated with improved cardiac Ca2+ release channel function in patients with heart failure.