Martin Thomas G, Hunt Dakota R, Ebmeier Christopher C, Dhand Abhishek P, Alamana Christina, Cleveland Joseph C, Graw Sharon L, Bruner Sarah, Bristow Michael R, Mestroni Luisa, Taylor Matthew R G, Burdick Jason A, Ambardekar Amrut V, Buttrick Peter M, Leinwand Leslie A
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, 80303, USA.
BioFrontiers Institute, University of Colorado Boulder, Boulder CO, 80303, USA.
bioRxiv. 2025 May 21:2025.05.16.654509. doi: 10.1101/2025.05.16.654509.
Restoration of cardiac function in patients with advanced heart failure is rare, and the molecular processes that regulate recovery are unknown. To identify potential mechanisms, we studied paired myocardial samples before and after left ventricular assist device therapy, where significant cardiac functional recovery occurred in ~25% of patients. We found that expression of the nuclear B isoform of Ca/calmodulin-dependent protein kinase IIδ (CaMKIIδ-B) inversely correlated with recovery. Furthermore, increased phosphorylation near the CaMKIIδ-B nuclear localization signal in non-responders prevented its auto-activation dependent nuclear translocation. Expression of a cytoplasm-restricted CaMKIIδ-B in cardiomyocytes dramatically remodeled the phospho-proteome and impaired contractility, while a nuclear-competent version did not. Modulating CaMKIIδ subcellular localization may thus represent a therapeutic strategy for advanced heart failure.
晚期心力衰竭患者心脏功能的恢复很少见，且调节恢复的分子过程尚不清楚。为了确定潜在机制，我们研究了左心室辅助装置治疗前后的配对心肌样本，约25%的患者出现了显著的心脏功能恢复。我们发现，钙/钙调蛋白依赖性蛋白激酶IIδ（CaMKIIδ）的核B亚型（CaMKIIδ-B）的表达与恢复呈负相关。此外，无反应者中CaMKIIδ-B核定位信号附近磷酸化增加，阻止了其依赖自身激活的核转位。心肌细胞中细胞质限制型CaMKIIδ-B的表达显著重塑了磷酸化蛋白质组并损害了收缩性，而具有核活性的版本则没有。因此，调节CaMKIIδ的亚细胞定位可能代表一种晚期心力衰竭的治疗策略。
