Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
J Cell Physiol. 2019 Jul;234(7):11587-11601. doi: 10.1002/jcp.27791. Epub 2018 Nov 29.
Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca overload. In this study, we investigated the effects of ranolazine on pressure overload-induced cardiac hypertrophy and heart failure in mice.
Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca release and increased SR Ca leak. Ranolazine restored aberrant SR Ca handling induced by pressure overload. Ranolazine also suppressed Na overload induced in the failing heart, and restored Na -induced Ca overload in an sodium-calcium exchanger (NCX)-dependent manner. Ranolazine suppressed the Ca -dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor-2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T-cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER-initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER-initiated cardiomyocyte apoptosis.
Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload-induced cardiac hypertrophy and systolic and diastolic function by restoring Na and Ca handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.
心肌肥厚和心力衰竭的特征是晚期钠电流增加和钙处理异常。雷诺嗪是晚期钠电流的选择性抑制剂，可减少钠积累和钙超载。在这项研究中，我们研究了雷诺嗪对压力超负荷诱导的小鼠心肌肥厚和心力衰竭的影响。
选择性抑制剂雷诺嗪抑制晚期钠电流，可抑制慢性主动脉缩窄（TAC）诱导的压力超负荷小鼠的心肌肥厚和纤维化，并改善超声心动图、血流动力学和组织学分析评估的心脏功能。TAC 小鼠心室肌细胞的钙成像显示，SR 钙释放异常和 SR 钙泄漏增加。雷诺嗪恢复了压力超负荷引起的异常 SR 钙处理。雷诺嗪还抑制了衰竭心脏中的钠过载，并以钠钙交换体（NCX）依赖的方式恢复了钠诱导的钙超载。雷诺嗪抑制了钙调蛋白（CaM）/钙调蛋白依赖性激酶 II/肌细胞增强因子 2（MEF2）和钙调蛋白/钙调蛋白依赖性激酶 II/钙调神经磷酸酶/激活 T 细胞核因子（NFAT）等由压力超负荷触发的肥厚信号通路。压力超负荷还延长了内质网（ER）应激，导致 ER 启动的细胞凋亡，而晚期钠电流或 NCX 的抑制减轻了 ER 应激和 ER 启动的心肌细胞凋亡。
我们的研究表明，雷诺嗪抑制晚期钠电流可通过恢复钠和钙处理、抑制下游肥厚途径和 ER 应激，改善压力超负荷引起的心肌肥厚和收缩及舒张功能。晚期钠电流的抑制可能为心肌肥厚和心力衰竭提供一种新的治疗策略。
