脑源性神经营养因子(BDNF)/原肌球蛋白相关激酶B(TrkB)通路与缺血性心脏病(IHD)相关。7,8-二羟基黄酮(7,8-DHF),BDNF模拟物,是TrkB的有效激动剂。我们旨在研究7,8-DHF对心肌缺血的影响和潜在机制。结扎冠状动脉左前降支建立小鼠心肌缺血模型。缺血后2天腹膜内施用7,8-DHF(5mg/kg),持续4周。超声心动图,HE染色和透射电镜检查功能,心脏的组织学和超微结构。H9c2细胞用过氧化氢(H2O2)处理,7,8-DHF或TrkB抑制剂ANA-12。7,8-DHF对细胞活力的影响,检查线粒体膜电位(MMP)和线粒体超氧化物的产生。此外,线粒体裂变和线粒体动力学的蛋白质表达(Mfn2[mitofusin2],OPA1[视神经萎缩1],通过mitotracker绿色染色和westernblot检测到Drp1[dynamin相关蛋白1]和Fis-1[fission1]),分别。7,8-DHF减轻心肌缺血小鼠的心功能障碍和心肌细胞异常。此外,7,8-DHF增加细胞活力并减少细胞死亡,同时改善MMP,抑制线粒体超氧化物并防止H2O2处理的H9c2细胞的过度线粒体裂变。ANA-12拮抗7,8-DHF的细胞保护作用。机械上,7,8-DHF抑制L-OPA1向S-OPA1的OMA1依赖性转化,其被Akt抑制剂消除。总之,7,8-DHF通过抑制OPA1的蛋白水解裂解来保护心脏缺血性损伤。这些发现提供了7,8-DHF对线粒体动力学的新药理作用和IHD的新潜在靶标。
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.