Phospholamban as a therapeutic modality in heart failure.
Phospholamban as a therapeutic modality in heart failure.
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DOI：
10.1002/0470029331.ch10
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发表时间：
2006
影响因子：
--
通讯作者：
G. Chu;E. Kranias
中科院分区：
文献类型：
--
作者：
G. Chu;E. Kranias
衰竭心脏舒张Ca2+升高和舒张功能受损反映了肌浆网ca - atp酶（SERCA2）功能的恶化，其活性受磷蛋白（PLN）调节。PLN是SERCA2的Ca2+亲和力和心脏收缩性的可逆抑制剂。对转基因小鼠模型的研究表明，PLN磷酸化的水平和程度对调节基础Ca2+处理和收缩性至关重要。相应地，实验和人类心力衰竭的收缩力下降部分归因于PLN抑制作用的增强，原因是：(a) PLN/SERCA2的增加；(b) PLN磷酸化降低。PLN磷酸化减弱与1型磷酸酶增加有关，这反映了其抑制剂1的去磷酸化或失活。事实上，PLN消融在一些心力衰竭小鼠模型中成功地挽救了心脏重构和功能障碍，抑制磷酸酶活性恢复了衰竭大鼠心脏的收缩参数。最近，两种与PLN缺失或持续去磷酸化相关的人类PLN突变与扩张型心肌病有关。因此，PLN调节似乎对人类至关重要，对高等哺乳动物物种PLN功能的进一步研究可能会为其作为心力衰竭治疗方式的潜力提供见解。
Increases in diastolic Ca2+ and impaired relaxation in failing hearts have been suggested to reflect the deteriorated function of the sarcoplasmic reticulum Ca-ATPase (SERCA2), whose activity is regulated by phospholamban (PLN). PLN is a reversible inhibitor of SERCA2's Ca2+ affinity and cardiac contractility. Studies in genetically altered mouse models have demonstrated that the levels and the degree of PLN phosphorylation are critical in modulating basal Ca2+ handling and contractility. Correspondingly, the depressed contractility in experimental and human heart failure is partially attributed to increased inhibition by PLN due to: (a) increases in PLN/SERCA2; and (b) decreases in PLN phosphorylation. The attenuated PLN phosphorylation is associated with increased type 1 phosphatase, which reflects dephosphorylation or inactivation of its inhibitor 1. Indeed PLN ablation was successful in rescuing cardiac remodelling and dysfunction in several heart failure mouse models, and inhibition of the phosphatase activity restored contractile parameters in failing rat hearts. Recently, two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy. Thus, PLN modulation appears to be of paramount importance in humans, and further investigation into PLN function in higher mammalian species may provide insights into its potential as a therapeutic modality in heart failure.