Division of Cardiology, Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty Street, Box 250773, Charleston, SC 29425, USA.
J Mol Cell Cardiol. 2010 Feb;48(2):342-51. doi: 10.1016/j.yjmcc.2009.11.007. Epub 2009 Nov 27.
The Na(+)-Ca(2+) exchanger gene (Ncx1) is upregulated in hypertrophy and is often found elevated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. beta-Adrenergic receptor (beta-AR) signaling plays an important role in the regulation of calcium homeostasis in the cardiomyocyte, but chronic activation in periods of cardiac stress contributes to heart failure by mechanisms which include Ncx1 upregulation. Here, using a Ca(2+)/calmodulin-dependent protein kinase II (CaMKIIdelta(c)) null mouse, we demonstrate that beta-AR-stimulated Ncx1 upregulation is dependent on CaMKII. beta-AR-stimulated Ncx1 expression is mediated by activator protein 1 (AP-1) factors and is independent of cAMP-response element-binding protein (CREB) activation. The MAP kinases (ERK1/2, JNK and p38) are not required for AP-1 factor activation. Chromatin immunoprecipitation demonstrates that beta-AR stimulation activates the ordered recruitment of JunB homodimers, which then are replaced by c-Jun homodimers binding to the proximal AP-1 elements of the endogenous Ncx1 promoter. In conclusion, this work has provided insight into the intracellular signaling pathways and transcription factors regulating Ncx1 gene expression in a chronically beta-AR-stimulated heart.
钠钙交换体基因（Ncx1）在心肌肥厚中上调，并且在心力衰竭终末期经常升高。研究表明，其表达的变化导致收缩功能障碍。β-肾上腺素能受体（β-AR）信号在心肌细胞钙稳态的调节中起着重要作用，但在心脏应激期间的慢性激活通过包括 Ncx1 上调在内的机制导致心力衰竭。在这里，我们使用钙/钙调蛋白依赖性蛋白激酶 II（CaMKIIdelta(c)）缺失小鼠，证明β-AR 刺激的 Ncx1 上调依赖于 CaMKII。β-AR 刺激的 Ncx1 表达由激活蛋白 1（AP-1）因子介导，并且独立于 cAMP 反应元件结合蛋白（CREB）的激活。MAP 激酶（ERK1/2、JNK 和 p38）不参与 AP-1 因子的激活。染色质免疫沉淀表明，β-AR 刺激激活 JunB 同源二聚体的有序募集，然后被结合到内源性 Ncx1 启动子近端 AP-1 元件的 c-Jun 同源二聚体取代。总之，这项工作深入了解了在慢性β-AR 刺激的心脏中调节 Ncx1 基因表达的细胞内信号通路和转录因子。
