Department of Pharmacology, University of California Davis, Davis, CA, USA.
Department of Pharmacology, University of California Davis, Davis, CA, USA.
J Mol Cell Cardiol. 2019 Feb;127:246-259. doi: 10.1016/j.yjmcc.2019.01.001. Epub 2019 Jan 8.
Calcium/calmodulin-dependent protein kinase II (CaMKII) is upregulated in diabetes and significantly contributes to cardiac remodeling with increased risk of cardiac arrhythmias. Diabetes is frequently associated with atrial fibrillation, coronary artery disease, and heart failure, which may further enhance CaMKII. Activation of CaMKII occurs downstream of neurohormonal stimulation (e.g. via G-protein coupled receptors) and involve various posttranslational modifications including autophosphorylation, oxidation, S-nitrosylation and O-GlcNAcylation. CaMKII signaling regulates diverse cellular processes in a spatiotemporal manner including excitation-contraction and excitation-transcription coupling, mechanics and energetics in cardiac myocytes. Chronic activation of CaMKII results in cellular remodeling and ultimately arrhythmogenic alterations in Ca handling, ion channels, cell-to-cell coupling and metabolism. This review addresses the detrimental effects of the upregulated CaMKII signaling to enhance the arrhythmogenic substrate and trigger mechanisms in the heart. We also briefly summarize preclinical studies using kinase inhibitors and genetically modified mice targeting CaMKII in diabetes. The mechanistic understanding of CaMKII signaling, cardiac remodeling and arrhythmia mechanisms may reveal new therapeutic targets and ultimately better treatment in diabetes and heart disease in general.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）在糖尿病中上调，并显著促进心脏重构，增加心律失常的风险。糖尿病常与心房颤动、冠状动脉疾病和心力衰竭相关，这可能进一步增强 CaMKII。CaMKII 的激活发生在神经激素刺激的下游（例如通过 G 蛋白偶联受体），并涉及多种翻译后修饰，包括自磷酸化、氧化、S-亚硝基化和 O-GlcNAc 化。CaMKII 信号以时空方式调节多种细胞过程，包括心肌细胞的兴奋-收缩偶联和兴奋-转录偶联、力学和能量代谢。CaMKII 的慢性激活导致细胞重构，并最终导致钙处理、离子通道、细胞间偶联和代谢的心律失常改变。这篇综述讨论了上调的 CaMKII 信号增强心律失常底物和触发心脏机制的有害作用。我们还简要总结了使用激酶抑制剂和针对糖尿病中 CaMKII 的基因修饰小鼠的临床前研究。对 CaMKII 信号、心脏重构和心律失常机制的机制理解可能揭示新的治疗靶点，并最终改善糖尿病和一般心脏病的治疗。
