Involvement of neurotrophic signaling in doxorubicin‑induced cardiotoxicity

Liao,Dehua; Zhang,Chen; Liu,Ni; Cao,Lizhi; Wang,Changshui; Feng,Qingyan; Yao,Dunwu; Long,Minghui; Jiang,Pei

doi:10.3892/etm.2019.8276

Involvement of neurotrophic signaling in doxorubicin‑induced cardiotoxicity

Authors:
- Dehua Liao
- Chen Zhang
- Ni Liu
- Lizhi Cao
- Changshui Wang
- Qingyan Feng
- Dunwu Yao
- Minghui Long
- Pei Jiang
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Affiliations: Department of Pharmacy, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China, Department of Cardiology, Jining First People's Hospital, Jining Medical University, Jining, Shandong 272000, P.R. China, Institute of Clinical Pharmacy and Pharmacology, Jining First People's Hospital, Jining Medical University, Jining, Shandong 272000, P.R. China, Department of Neurology, Jining First People's Hospital, Jining Medical University, Jining, Shandong 272000, P.R. China
Published online on: December 4, 2019 https://doi.org/10.3892/etm.2019.8276
Pages: 1129-1135

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Abstract

Dose dependent cardiotoxicity is the primary side effect of doxorubicin (DOX), but the underlying molecular mechanisms remain unclear. An increasing amount of evidence has demonstrated that neurotrophic signaling plays a pivotal role in both neurons and the heart, but the biological association between neurotrophic signaling and DOX‑induced cardiotoxicity remains unknown. The present study determined the level of neurotrophins and their receptors in the heart of rats following DOX administration. DOX was administered 7 times at a dose of 2.5 mg/kg once every 2 days via intraperitoneal injection. The present study revealed that cardiac injury parameters, such as creatine kinase (CK), creatine kinase‑myocardial bound, lactate dehydrogenase, troponin T and aspartate transaminase in serum were significantly increased in the DOX group. Both the gene and protein expression of brain‑derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart were markedly decreased following DOX treatment. Notably, the protein level of BDNF in the serum was inhibited in DOX‑treated rats, whereas DOX induced a significant increase in the protein level of NGF in the serum. DOX induced a significant decrease in the level of tropomyosin‑associated kinase A (TrkA) and the ratio of pTrkA/TrkA and pTrkB/TrkB. Furthermore, the administration of DOX suppressed downstream protein kinase B and extracellular signal regulated kinase phosphorylation. The present study first demonstrated that BDNF/TrkB signaling and NGF/TrkA signaling were altered by DOX, which indicated that neurotrophic signaling was involved in DOX‑induced cardiotoxicity.

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