Brain-derived neurotrophic factor mimetic, 7,8-dihydroxyflavone, protects against myocardial ischemia by rebalancing optic atrophy 1 processing.

Abstract

Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway is associated with ischemic heart diseases (IHD). 7,8-dihydroxyflavone (7,8-DHF), BDNF mimetic, is a potent agonist of TrkB. We aimed to investigate the effects and the underlying mechanisms of 7,8-DHF on cardiac ischemia. Myocardial ischemic mouse model was induced by ligation of left anterior descending coronary artery. 7,8-DHF (5 mg/kg) was administered intraperitoneally two days after ischemia for four weeks. Echocardiography, HE staining and transmission electron microscope were used to examine the function, histology and ultrastructure of the heart. H9c2 cells were treated with hydrogen peroxide (H2O2), 7,8-DHF or TrkB inhibitor ANA-12. The effects of 7,8-DHF on cell viability, mitochondrial membrane potential (MMP) and mitochondrial superoxide generation were examined. Furthermore, mitochondrial fission and protein expression of mitochondrial dynamics (Mfn2 [mitofusin 2], OPA1 [optic atrophy 1], Drp1 [dynamin-related protein 1] and Fis-1 [fission 1]) was detected by mitotracker green staining and western blot, respectively. 7,8-DHF attenuated cardiac dysfunction and cardiomyocyte abnormality of myocardial ischemic mice. Moreover, 7,8-DHF increased cell viability and reduced cell death accompanied by improving MMP, inhibiting mitochondrial superoxide and preventing excessive mitochondrial fission of H2O2-treated H9c2 cells. The cytoprotective effects of 7,8-DHF were antagonized by ANA-12. Mechanistically, 7,8-DHF repressed OMA1-dependent conversion of L-OPA1 into S-OPA1, which was abolished by Akt inhibitor. In conclusion, 7,8-DHF protects against cardiac ischemic injury by inhibiting the proteolytic cleavage of OPA1. These findings provide a novel pharmacological effect of 7,8-DHF on mitochondrial dynamics and a new potential target for IHD.

• Authors: Zhen Wang, Shi-Peng Wang, Qun Shao, Pei-Feng Li, Yue Sun, Lan-Zi Luo, Xiu-Qing Yan, Zi-Yi Fan, Juan Hu, Jing Zhao, Peng-Zhou Hang, Zhi-Min Du
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 145 Pg. 187-197 (12 2019) ISSN: 1873-4596 [Electronic] United States
• PMID: 31574344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 6,7-dihydroxyflavone
• Brain-Derived Neurotrophic Factor
• Flavones
• Membrane Glycoproteins
• Neuroprotective Agents
• Hydrogen Peroxide
• Ntrk2 protein, mouse
• Protein-Tyrosine Kinases
• GTP Phosphohydrolases
• OPA1 protein, human

Topics

• Animals
• Brain-Derived Neurotrophic Factor (genetics, pharmacology)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Flavones (pharmacology)
• GTP Phosphohydrolases (chemistry, genetics)
• Heart (drug effects, physiopathology)
• Humans
• Hydrogen Peroxide (metabolism)
• Membrane Glycoproteins (genetics)
• Mice
• Mitochondria (drug effects, metabolism)
• Mitochondrial Dynamics
• Myocardial Ischemia (drug therapy, genetics, pathology)
• Neuroprotective Agents (pharmacology)
• Optic Atrophy, Autosomal Dominant (drug therapy, genetics, pathology)
• Protein-Tyrosine Kinases (genetics)