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

ABSTRACT: Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-kappa B (NF-?B) 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-?B. DOX activated CaMKII and NF-?B 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-?B 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-?B and cardiomyocyte apoptosis. Inhibition of NF-?B 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-?B in mouse hearts. Nifedipine (10?mg/kg/day) significantly suppressed DOX-induced phosphorylation of CaMKII and NF-?B 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-?B pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.

SUBMITTER: Ikeda S

PROVIDER: S-EPMC6614470 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Ikeda Soichiro S Matsushima Shouji S Okabe Kosuke K Ikeda Masataka M Ishikita Akihito A Tadokoro Tomonori T Enzan Nobuyuki N Yamamoto Taishi T Sada Masashi M Deguchi Hiroko H Morimoto Sachio S Ide Tomomi T Tsutsui Hiroyuki H

Scientific reports 20190708 1

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 ...[more]

PMID: 31285514

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

Publications

Blockade of L-type Ca<sup>2+</sup> channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.

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Dataset Information

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

Publications

Blockade of L-type Ca<sup>2+</sup> channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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