Alterations of Phospholamban Function Can Exhibit Cardiotoxic Effects Independent of Excessive Sarcoplasmic Reticulum Ca2+-ATPase Inhibition
Alterations of Phospholamban Function Can Exhibit Cardiotoxic Effects Independent of Excessive Sarcoplasmic Reticulum Ca2+-ATPase Inhibition
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DOI：
10.1161/circulationaha.108.783506
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发表时间：
2009-01-27
期刊：
影响因子：
37.8
通讯作者：
Lohse, Martin J.
中科院分区：
文献类型：
--
作者：
Schmitt, Joachim P.;Ahmad, Ferhaan;Lohse, Martin J.
受磷蛋白（phospholamban，PLN）对肌浆网Ca ~（2+）-ATP酶（sarco（endo）plasmic reticulum Ca ~（2+）-ATPase，SERCA ~（2a））活性的强烈抑制可导致心肌收缩力下降，导致扩张型心肌病和心力衰竭。方法和结果-由于PLNR 9 C主要通过防止野生型PLN失活来抑制SERCA 2a，因此通过产生携带PLNR 9 C转基因和2，1，或0个内源PLN等位基因（分别为PLN+/+ + TgPLN（R9 C）、PLN+/+ + TgPLN（R9 C）和PLN-/- + TgPLN（R9 C））。与PLN+/+ + TgPLN（R9 C）小鼠相比，PLN-/- + TgPLN（R9 C）心脏表现出加速的肌浆网Ca 2+摄取速率和改善的血液动力学，但对β-肾上腺素能刺激的反应仍然很差，因为PLNR 9 C损害野生型和突变型PLN两者的蛋白激酶A介导的磷酸化。PLN+/+ + TgPLNR 9 C小鼠在21 +/-6周时死于心力衰竭，而杂合PLN+/- + TgPLN（R9 C）小鼠存活至48 +/-11周，PLN-/- + TgPLN（R9 C）小鼠存活至66 +/-19周，野生型小鼠存活至94 +/-27周（P < 0.001）。尽管年轻PLN-/- + TgPLN（R9 C）小鼠中的Ca 2+再摄取动力学超过了在野生型对照动物中测量的那些，但是单独的该参数不足以防止扩张型心肌病的最终发展。其改变SERCA 2a活性水平的能力降低，导致心力衰竭，尽管肌浆网Ca 2+再摄取快速。（循环。2009; 119：436-444）。
Background-Low activity of the sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA2a) resulting from strong inhibition by phospholamban (PLN) can depress cardiac contractility and lead to dilated cardiomyopathy and heart failure. Here, we investigated whether PLN exhibits cardiotoxic effects via mechanisms other than chronic inhibition of SERCA2a by studying a PLN mutant, PLNR9C, that triggers cardiac failure in humans and mice.Methods and Results-Because PLNR9C inhibits SERCA2a mainly by preventing deactivation of wild-type PLN, SERCA2a activity could be increased stepwise by generating mice that carry a PLNR9C transgene and 2, 1, or 0 endogenous PLN alleles (PLN+/+ + TgPLN(R9C), PLN+/+ + TgPLN(R9C), and PLN-/- + TgPLN(R9C), respectively). PLN-/- + TgPLN(R9C) hearts demonstrated accelerated sarcoplasmic reticulum Ca2+ uptake rates and improved hemodynamics compared with PLN+/+ + TgPLN(R9C) mice but still responded poorly to beta-adrenergic stimulation because PLNR9C impairs protein kinase A-mediated phosphorylation of both wild-type and mutant PLN. PLN+/+ + TgPLNR9C mice died of heart failure at 21 +/- 6 weeks, whereas heterozygous PLN+/- + TgPLN(R9C) mice survived to 48 +/- 11 weeks, PLN-/- + TgPLN(R9C) mice to 66 +/- 19 weeks, and wild-type mice to 94 +/- 27 weeks (P < 0.001). Although Ca2+ reuptake kinetics in young PLN-/- + TgPLN(R9C) mice exceeded those measured in wild-type control animals, this parameter alone was not sufficient to prevent the eventual development of dilated cardiomyopathy.Conclusions-The data demonstrate an association between the dose-dependent inhibition of SERCA2a activity by PLNwt and the time of onset of heart failure and show that a weak inhibitor of SERCA2a, PLNR9C, which is diminished in its ability to modify the level of SERCA2a activity, leads to heart failure despite fast sarcoplasmic reticulum Ca2+ reuptake. (Circulation. 2009; 119: 436-444.)