LCN2 deficiency ameliorates doxorubicin-induced cardiomyopathy in mice.

Hye Min Jang, Jong Youl Lee, Hyeong Seok An, Yu Jeong Ahn, Eun Ae Jeong, Hyun Joo Shin, Kyung Eun Kim, Jaewoong Lee, Jin Sin Koh, Gu Seob Roh

Biochemical and biophysical research communications 2022 Jan 15

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Doxorubicin (DOX) is an effective anticancer drug with the side effect of irreparable cardiomyopathy. Lipocalin-2 (LCN2) has been identified as an important regulator of oxidative stress and inflammation in cardiovascular disease pathophysiology. Here, we demonstrate that LCN2 deletion increases autophagic flux in the DOX-treated hearts. Mice were injected intraperitoneally six times with 30 mg/kg DOX. Echocardiography showed that DOX-treated wild-type (WT) mice had markedly weaker cardiac function compared to saline-treated WT mice. In DOX-treated LCN2 knockout (KO) mice, cardiac function was partially restored. Histological analysis showed a reduction in cardiomyocyte diameter in DOX-treated WT mice that was ameliorated in DOX-treated LCN2KO mice. Cardiac levels of phosphorylated signal transducer and activator of transcription 3, LCN2, heme oxygenase-1, and NAD (P) H dehydrogenase were markedly greater in DOX-treated WT mice than in DOX-treated LCN2KO mice. Light chain 3B (LC3B)II expression was higher in DOX-treated WT mice, but lower in DOX-treated LCN2KO mice when compared to saline-treated WT mice. Less co-localization of LC3B and lysosomal-associated membrane protein 1 was observed in DOX-treated WT mice than in DOX-treated LCN2KO mice. LCN2 co-localized with LC3B-stained cells in the DOX-treated WT mouse heart, but not in the DOX-treated LCN2KO mouse heart. These findings indicate that the cardiotoxic effect of DOX is due to autophagosome accumulation mediated by LCN2 upregulation and that LCN2 may inhibit autophagic flux, leading to DOX-induced cardiomyopathy. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Hye Min Jang, Jong Youl Lee, Hyeong Seok An, Yu Jeong Ahn, Eun Ae Jeong, Hyun Joo Shin, Kyung Eun Kim, Jaewoong Lee, Jin Sin Koh, Gu Seob Roh. LCN2 deficiency ameliorates doxorubicin-induced cardiomyopathy in mice. Biochemical and biophysical research communications. 2022 Jan 15;588:8-14