Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
PLoS One. 2011;6(9):e24724. doi: 10.1371/journal.pone.0024724. Epub 2011 Sep 13.
Ca²⁺/calmodulin-dependent protein kinase II δB (CaMKIIδB) is one of the predominant isoforms of CaMKII in the heart. The precise role of CaMKIIδB in the transcriptional cross-talk of Ca²⁺-handling proteins during heart failure remains unclear. In this work, we aim to determine the mechanism of CaMKIIδB in modulating the expression of sarcolemmal Na⁺-Ca²⁺ exchange (NCX1). We also aim to address the potential effects of calmodulin antagonism on the imbalance of NCX1 and sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA) during heart failure. Eight weeks after transverse aortic constriction (TAC)-induced heart failure in mice, we found that the heart weight/tibia length (HW/TL) ratio and the lung weight/body weight (LW/BW) ratio increased by 59% and 133%, respectively. We further found that the left ventricle-shortening fraction decreased by 40% compared with the sham-operated controls. Immunoblotting revealed that the phosphorylation of CaMKIIδB significantly increased 8 weeks after TAC-induced heart failure. NCX1 protein levels were also elevated, whereas SERCA2 protein levels decreased in the same animal model. Moreover, transfection of active CaMKIIδB significantly increased NCX1 protein levels in adult mouse cardiomyocytes via class IIa histone deacetylase (HDAC)/myocyte enhancer factor-2 (MEF2)-dependent signaling. In addition, pharmacological inhibition of calmodulin/CaMKIIδB activity improved cardiac function in TAC mice, which partially normalized the imbalance between NCX1 and SERCA2. These data identify NCX1 as a cellular target for CaMKIIδB. We also suggest that the CaMKIIδB-induced imbalance between NCX1 and SERCA2 is partially responsible for the disturbance of intracellular Ca²⁺ homeostasis and the pathological process of heart failure.
钙调蛋白依赖性蛋白激酶 II δB（CaMKIIδB）是心脏中 CaMKII 的主要同工型之一。在心力衰竭过程中，CaMKIIδB 在钙处理蛋白的转录串扰中的确切作用尚不清楚。在这项工作中，我们旨在确定 CaMKIIδB 调节肌浆网 Na⁺-Ca²⁺交换（NCX1）蛋白表达的机制。我们还旨在解决钙调蛋白拮抗作用对心力衰竭期间 NCX1 和肌浆内质网 Ca²⁺ATP 酶（SERCA）失衡的潜在影响。在小鼠横主动脉缩窄（TAC）诱导的心力衰竭 8 周后，我们发现心脏重量/胫骨长度（HW/TL）比值和肺重量/体重（LW/BW）比值分别增加了 59%和 133%。我们进一步发现，与假手术对照相比，左心室缩短分数降低了 40%。免疫印迹显示，TAC 诱导的心力衰竭 8 周后 CaMKIIδB 的磷酸化显著增加。NCX1 蛋白水平也升高，而同一动物模型中的 SERCA2 蛋白水平降低。此外，活性 CaMKIIδB 的转染通过 IIa 类组蛋白去乙酰化酶（HDAC）/肌细胞增强因子-2（MEF2）依赖性信号通路显著增加成年小鼠心肌细胞中的 NCX1 蛋白水平。此外，钙调蛋白/CaMKIIδB 活性的药理学抑制改善了 TAC 小鼠的心脏功能，部分纠正了 NCX1 和 SERCA2 之间的失衡。这些数据将 NCX1 确定为 CaMKIIδB 的细胞靶标。我们还表明，CaMKIIδB 诱导的 NCX1 和 SERCA2 之间的失衡部分导致细胞内 Ca²⁺稳态紊乱和心力衰竭的病理过程。
