Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
J Mol Cell Cardiol. 2010 Jun;48(6):1206-14. doi: 10.1016/j.yjmcc.2010.02.009. Epub 2010 Feb 17.
Chronic pressure overload to the heart leads to cardiac hypertrophy and failure through processes that involve reorganization of subcellular compartments and alteration of established signaling mechanisms. To identify proteins contributing to this process, we examined changes in nuclear-associated myofilament proteins as the murine heart undergoes progressive hypertrophy following pressure overload. Calsarcin-1, a negative regulator of calcineurin signaling in the heart, was found to be enriched in cardiac nuclei and displays increased abundance following pressure overload through a mechanism that is decoupled from transcriptional regulation. Using proteomics, we identified novel processing of this protein in the setting of cardiac injury and identified four residues subject to modification by phosphorylation. These studies are the first to determine mechanisms regulating calsarcin abundance during hypertrophy and failure and reveal the first evidence of post-translational modifications of calsarcin-1 in the myocardium. Overall, the findings expand the roles of calsarcins to include nuclear tasks during cardiac growth.
慢性心脏压力超负荷通过涉及亚细胞区室重排和既定信号机制改变的过程导致心肌肥厚和衰竭。为了鉴定参与这一过程的蛋白质，我们研究了在小鼠心脏经历压力超负荷后逐渐发生肥厚时与核相关的肌丝蛋白的变化。钙调磷酸酶信号的心脏负调节剂钙调蛋白 1（Calsarcin-1）在心脏中被发现富含于心肌细胞核中，并通过一种与转录调控脱耦的机制在压力超负荷后增加。通过蛋白质组学，我们在心脏损伤的情况下鉴定了该蛋白的新型加工，并确定了四个残基可通过磷酸化修饰。这些研究首次确定了调节钙调蛋白在肥厚和衰竭期间丰度的机制，并首次揭示了心肌中钙调蛋白 1 的翻译后修饰。总的来说，这些发现将钙调蛋白的作用扩展到心脏生长过程中的核任务。
