Structural and functional implications of the phospholamban hinge domain:: impaired SR Ca2+ uptake as a primary cause of heart failure
Structural and functional implications of the phospholamban hinge domain:: impaired SR Ca2+ uptake as a primary cause of heart failure
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DOI：
10.1016/s0008-6363(02)00541-2
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发表时间：
2002-11-01
影响因子：
10.8
通讯作者：
Kranias, EG
中科院分区：
文献类型：
--
作者：
Schmidt, AG;Zhai, J;Kranias, EG
目的：肌浆网（SR）在心力衰竭发生发展中的作用存在争议。我们测试了这一假设，即SR钙螯合的损害可能是进行性左心室（LV）功能障碍的主要原因，受磷蛋白铰链结构域可能在这个过程中是至关重要的。方法：在受磷蛋白基因敲除小鼠的心脏室中引入受磷蛋白铰链结构域突变体（PLB/N27 A）。采用综合方法在结构、细胞、整个器官和完整动物水平上表征所得心脏表型。结果：NMR分析揭示了突变体受磷蛋白中残基Q22至F35之间的α-螺旋构型的确定改变。与野生型受磷蛋白相比，表达类似水平突变体的转基因株系表现出超抑制SR Ca 2 + ATP酶对Ca 2+的亲和力（EC 50 0.52 μ M），在琥珀酸盐支持的Ca 2+摄取测量中，这转化为对β-肾上腺素能刺激的松弛受损和衰减的反应。重要的是，在左心室扩张之前的突变心脏中观察到了一种钝化的力-频率关系。在年龄至10个月时，主要的舒张功能障碍进展为充血性心力衰竭，其特征在于诱导胎儿基因程序、心脏重塑、肺充血、收缩功能低下和早期死亡。结论：增加对Ca 2+隔离的抑制可能是导致心力衰竭的左心室功能障碍和心肌细胞重塑的发展的致病因素。此外，铰链结构域可能在传递PLB对SERCA的调节作用中起重要作用。(C)2002 Elsevier Science B. V.保留所有权利。
Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process. Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level. Results: NMR analysis revealed a defined alteration in the a-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 muM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to beta-adrenergic stimulation. Importantly, a blunted force-frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality. Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB's regulatory effects on SERCA. (C) 2002 Elsevier Science B.V. All rights reserved.