PMID- 30472367 OWN - NLM STAT- MEDLINE DCOM- 20191210 LR - 20211204 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 130 DP - 2019 Jan TI - Activation of cardiac TrkB receptor by its small molecular agonist 7,8-dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation. PG - 557-567 LID - S0891-5849(18)31682-4 [pii] LID - 10.1016/j.freeradbiomed.2018.11.024 [doi] AB - Brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) pathway has been revealed as a novel therapeutic target for several neurological diseases. Recently, small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) has received considerable attention as a novel potential candidate for the treatment of various BDNF-implicated human disorders. However, its roles in cardiac diseases are not fully understood. Here, the present study aimed to clarify the effects and mechanisms of 7,8-DHF on doxorubicin (Dox)-induced cardiotoxicity. Kunming mice and H9c2 cells were employed to investigate the functional role of 7,8-DHF both in vivo and in vitro. 7,8-DHF markedly increased cell viability and reduced cell death of Dox-treated cells. Meanwhile, 7,8-DHF significantly increased mitochondrial respiration, membrane potential, and optic atrophy 1 (OPA1) protein expression. 7,8-DHF improved cardiac function and attenuated cardiac injury in Dox mice model. Expression of AMP-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) was restored by 7,8-DHF. Furthermore, the protective role of 7,8-DHF was abolished by ANA-12 (a specific antagonist of TrkB). In elucidating the molecular mechanism, the phosphorylation of Akt was significantly increased while extracellular regulated protein kinase (ERK) was decreased after 7,8-DHF treatment. The regulatory effects of 7,8-DHF on STAT3 and AMPK was reversed by Akt inhibitor. In summary, 7,8-DHF attenuated Dox-induced cardiotoxicity by activating Akt and increasing mitochondrial oxidative phosphorylation and thereby regulating STAT3, AMPK, and ERK signals. The present study enhanced current understanding of TrkB receptor in the cardiovascular system and provided a novel target for prevention and treatment of heart diseases. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Zhao, Jing AU - Zhao J AD - Department of Cardiology, the First Affiliated Hospital of Harbin Medical University (Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University), Harbin 150001, PR China. FAU - Du, Jingjing AU - Du J AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Pan, Yang AU - Pan Y AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Chen, Tingting AU - Chen T AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Zhao, Lihui AU - Zhao L AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Zhu, Yanmeng AU - Zhu Y AD - Department of Pharmacology, Harbin Medical University, Harbin 150081, PR China. FAU - Chen, Yingfu AU - Chen Y AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Zheng, Yuyang AU - Zheng Y AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Liu, Yu AU - Liu Y AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China. FAU - Sun, Lihua AU - Sun L AD - Department of Pharmacology, Harbin Medical University, Harbin 150081, PR China. FAU - Hang, Pengzhou AU - Hang P AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China. Electronic address: hangpz@ems.hrbmu.edu.cn. FAU - Du, Zhimin AU - Du Z AD - Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China. Electronic address: dzm1956@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181122 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (6,7-dihydroxyflavone) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Flavones) RN - 0 (STAT3 Transcription Factor) RN - 80168379AG (Doxorubicin) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics MH - Cardiotoxicity/*drug therapy/pathology MH - Cell Survival/drug effects MH - Doxorubicin/toxicity MH - Flavones/*pharmacology MH - Gene Expression Regulation/drug effects MH - Heart/drug effects/physiopathology MH - Heart Diseases/chemically induced/*drug therapy/genetics/pathology MH - Humans MH - Mice MH - Mitochondria/drug effects/*genetics MH - Oxidative Phosphorylation/drug effects MH - Protein Kinases/genetics MH - Receptor, trkB/*genetics MH - STAT3 Transcription Factor/genetics MH - Signal Transduction/drug effects OTO - NOTNLM OT - 7,8-dihydroxyflavone OT - Akt OT - Cardiotoxicity OT - Doxorubicin OT - Mitochondria EDAT- 2018/11/26 06:00 MHDA- 2019/12/18 06:00 CRDT- 2018/11/26 06:00 PHST- 2018/09/21 00:00 [received] PHST- 2018/11/09 00:00 [revised] PHST- 2018/11/20 00:00 [accepted] PHST- 2018/11/26 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2018/11/26 06:00 [entrez] AID - S0891-5849(18)31682-4 [pii] AID - 10.1016/j.freeradbiomed.2018.11.024 [doi] PST - ppublish SO - Free Radic Biol Med. 2019 Jan;130:557-567. doi: 10.1016/j.freeradbiomed.2018.11.024. Epub 2018 Nov 22.