阻断 L 型钙通道通过抑制 CaMKII-NF-κB 通路减轻阿霉素诱导的心肌病。
Blockade of L-type Ca channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.
机构信息
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.
出版信息
Sci Rep. 2019 Jul 8;9(1):9850. doi: 10.1038/s41598-019-46367-6.
Ca/calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-kappa B (NF-κB) play crucial roles in pathogenesis of doxorubicin (DOX)-induced cardiomyopathy. Their activities are regulated by intracellular Ca. We hypothesized that blockade of L-type Ca channel (LTCC) could attenuate DOX-induced cardiomyopathy by regulating CaMKII and NF-κB. DOX activated CaMKII and NF-κB through their phosphorylation and increased cleaved caspase 3 in cardiomyocytes. Pharmacological blockade or gene knockdown of LTCC by nifedipine or small interfering RNA, respectively, suppressed DOX-induced phosphorylation of CaMKII and NF-κB and apoptosis in cardiomyocytes, accompanied by decreasing intracellular Ca concentration. Autocamtide 2-related inhibitory peptide (AIP), a selective CaMKII inhibitor, inhibited DOX-induced phosphorylation of NF-κB and cardiomyocyte apoptosis. Inhibition of NF-κB activity by ammonium pyrrolidinedithiocarbamate (PDTC) suppressed DOX-induced cardiomyocyte apoptosis. DOX-treatment (18 mg/kg via intravenous 3 injections over 1 week) increased phosphorylation of CaMKII and NF-κB in mouse hearts. Nifedipine (10 mg/kg/day) significantly suppressed DOX-induced phosphorylation of CaMKII and NF-κB and cardiomyocyte injury and apoptosis in mouse hearts. Moreover, it attenuated DOX-induced left ventricular dysfunction and dilatation. Our findings suggest that blockade of LTCC attenuates DOX-induced cardiomyocyte apoptosis via suppressing intracellular Ca elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）和核因子-κB（NF-κB）在阿霉素（DOX）诱导的心肌病发病机制中发挥关键作用。它们的活性受细胞内 Ca 的调节。我们假设，通过调节 CaMKII 和 NF-κB，L 型钙通道（LTCC）阻断可减轻 DOX 诱导的心肌病。DOX 通过其磷酸化和增加心肌细胞中裂解的 caspase 3 激活 CaMKII 和 NF-κB。硝苯地平或小干扰 RNA 分别通过药理学阻断或基因敲低 LTCC，抑制 DOX 诱导的 CaMKII 和 NF-κB 的磷酸化和心肌细胞凋亡，同时降低细胞内 Ca 浓度。钙调蛋白依赖性蛋白激酶 II 的选择性抑制剂 Autocamtide 2 相关抑制肽（AIP）抑制 DOX 诱导的 NF-κB 磷酸化和心肌细胞凋亡。通过铵吡啶二硫代氨基甲酸盐（PDTC）抑制 NF-κB 活性抑制 DOX 诱导的心肌细胞凋亡。DOX 处理（18mg/kg 通过静脉内 3 次注射，每周 1 次共 1 周）增加小鼠心脏中 CaMKII 和 NF-κB 的磷酸化。硝苯地平（10mg/kg/天）可显著抑制 DOX 诱导的 CaMKII 和 NF-κB 的磷酸化以及小鼠心脏中的心肌细胞损伤和凋亡。此外，它还减轻了 DOX 诱导的左心室功能障碍和扩张。我们的研究结果表明，LTCC 阻断通过抑制细胞内 Ca 升高和激活 CaMKII-NF-κB 通路减轻 DOX 诱导的心肌细胞凋亡。LTCC 阻滞剂可能是治疗 DOX 诱导的心肌病的潜在治疗剂。
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