Nifedipine Attenuates Doxorubicin-induced Cardiomyopathy by Suppressing CaMKII-NF-kB Pathway

Background: Activation of CaMKII induces cardiomyocyte death in doxorubicin (DOX)-induced cardiomyopathy. Nifedipine, L-type calcium channel blocker, has been shown to inhibit CaMKII activity in hypertrophic heart. The purpose of this study was to determine whether nifedipine could attenuate DOX-induced cardiomyopathy by inhibiting CaMKII activity and to elucidate its downstream signaling. Methods and Results: Mice were treated with DOX (18 mg/kg via 3 intravenous injections over 1 week) with or without subpressor dose of nifedipine (10 mg/kg/day). Two weeks after DOX treatment, nifedipine prevented DOX-induced decrease in left ventricular fractional shortening (25.7 ± 1.5% vs. 32.9 ± 0.3%, P < .05). Nifedipine decreased Dox-induced cardiomyocyte death as assessed by Billingham score (2.88 ± 0.25 vs. 1.88 ± 0.48 P < .05). It also inhibited DOX-induced phosphorylation of CaMKII and NF-kB, their active forms, by 42% and 30%, respectively (P < .05), in the heart. In cultured neonatal rat ventricular myocytes (NRVMs), DOX (10 µM, 24h) increased phosphorylated CaMKII and NF-kB and cleaved caspase-3, and LDH release, a marker of cell death. Treatment with nifedipine (10 µM, 24h) or autocamtide 2-related inhibitory peptide (AIP, 10 µM, 24h), a selective inhibitor of CaMKII, significantly suppressed DOX-induced increases in phosphorylated CaMKII, cleaved caspase-3 and LDH release in NRVMs, which was accompanied by a decrease in phosphorylated NF-kB. Conclusions: Nifedipine attenuated DOX-induced cardiomyopathy by suppressing CaMKII-NF-kB pathway. Therapeutic strategy designed to interfere with this pathway might be beneficial in its prevention.