Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy.
Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy.
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DOI：
10.1172/jci16738
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发表时间：
2003-03
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通讯作者：
Qiujing Song;A. Schmidt;H. Hahn;Andrew N. Carr;Beate Frank;L. Pater;Michael J Gerst;Karen B. Young;B. Hoit;B. McConnell;K. Haghighi;C. Seidman;J. Seidman;G. Dorn;E. Kranias
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文献类型：
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作者：
Qiujing Song;A. Schmidt;H. Hahn;Andrew N. Carr;Beate Frank;L. Pater;Michael J Gerst;Karen B. Young;B. Hoit;B. McConnell;K. Haghighi;C. Seidman;J. Seidman;G. Dorn;E. Kranias
心肌肥厚，无论是代偿的还是失代偿的，都与肌浆网(SR)钙(2+)循环抑制所致的心肌细胞收缩功能障碍有关。通过消融或抑制SR抑制剂磷脂蛋白(PLN)使Ca(2+)循环正常化，可以预防实验性扩张型心肌病的心力衰竭，是一种很有前途的治疗人类心力衰竭的方法。然而，恢复SR功能对原发性心肌肥厚的潜在益处尚不清楚，这是人类心力衰竭的常见先兆。因此，我们在两个特征明确且高度相关的肥厚和心力衰竭遗传小鼠模型-Galphaq过度表达和人类家族性肥厚性心肌病突变肌球蛋白结合蛋白C(MyBP-C(Mut))表达-中测试了PLN消融对纠正肥厚和收缩功能障碍的有效性。在两种模型中，PLN消融均使典型的延长的心肌细胞Ca(2+)瞬变正常化，并增强了无负荷缩短的分数，而SR Ca(2+)泵的含量没有改变。然而，在两种模型中，在体内心脏功能或肥厚方面都没有平行的改善。同样，与Galphaq过表达相关的JNK和钙调神经磷酸酶的激活也没有受到影响。因此，PLN消融使分离的心肌细胞的收缩功能恢复正常，但未能挽救由Galphaq通路激活或MyBP-C突变引起的心肌病表型。
Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.