Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway

Soichiro Ikeda, Shouji Matsushima, Kosuke Okabe, Masataka Ikeda, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Hiroko Deguchi, Sachio Morimoto, Tomomi Ide, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿記事

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Ca2+/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 Ca2+. We hypothesized that blockade of L-type Ca2+ 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 Ca2+ 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 Ca2+ elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.

元の言語英語
記事番号9850
ジャーナルScientific reports
9
発行部数1
DOI
出版物ステータス出版済み - 12 1 2019

All Science Journal Classification (ASJC) codes

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フィンガープリント Blockade of L-type Ca<sup>2+</sup> channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Ikeda, S., Matsushima, S., Okabe, K., Ikeda, M., Ishikita, A., Tadokoro, T., Enzan, N., Yamamoto, T., Sada, M., Deguchi, H., Morimoto, S., Ide, T., & Tsutsui, H. (2019). Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway. Scientific reports, 9(1), [9850]. https://doi.org/10.1038/s41598-019-46367-6