心力衰竭时线粒体稳态失衡的新机制：BDNF-TrkB-STAT3-AMPK

The imbalance of mitochondrial homeostasis is an important cause of myocardial damage and dysfunction during heart failure, but its exact mechanism is unclear and new targets for intervention are still lacking. Studies have confirmed that brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) axis plays an important role in the nervous system. Recently, it has been uncovered that BDNF/TrkB pathway could directly regulate the physiological function of normal heart, but its role in heart failure remains to be elucidated. We previously found the protective effect of BDNF against myocardial apoptosis. Furthermore, preliminary studies suggested that protein expression of BDNF and TrkB phosphorylation decreased in heart failure, and activation of TrkB receptor by its specific agonist 7,8-DHF significantly enhanced mitochondrial respiratory function, inhibited mitochondrial fission, and regulated signal transducers and activators of transcription (STAT3) and AMP-activated protein kinase (AMPK) phosphorylation level. Therefore, we hypothesize that BDNF/TrkB pathway protects the failing myocardium by regulating STAT3/AMPK signaling and thereby mitochondrial homeostasis. The aims of this project include: (1) Clarifying the critical role of BDNF/TrkB in cardiomyocyte injury and mitochondrial dysfunction in heart failure; (2) Uncovering whether the regulatory role of TrkB in mitochondrial function after endocytosis is dependent on STAT3 phosphorylation; (3) Exploring mechanism underlying AMPK feedback regulates the mitochondrial homeostasis and BDNF expression. In this study, novel mechanism of mitochondria homeostasis imbalance in heart failure was revealed based on in vivo and in vitro studies as well as knockout and overexpression technologies, to provide new targets for the prevention and control of heart failure.

线粒体稳态失衡是心衰时心肌细胞损伤和功能障碍的重要原因，但其确切机制不清，仍缺乏新的干预靶点。研究证实BDNF/TrkB在神经系统中具有重要作用，近年来研究发现其可直接调节正常心脏生理功能，但在心衰中的作用有待揭示。我们首次发现BDNF具有抗心肌细胞凋亡作用。预实验发现心衰时心肌BDNF及TrkB受体磷酸化水平降低，激动TrkB受体可改善线粒体呼吸功能障碍，抑制线粒体过度分裂；并能调控STAT3及AMPK磷酸化水平。因此，我们假设BDNF/TrkB通过STAT3/AMPK信号调节线粒体稳态保护衰竭心肌。本项目拟研究：①BDNF/TrkB在心衰时心肌损伤及线粒体功能异常中的作用；②TrkB受体内吞后介导STAT3磷酸化对线粒体功能的调节机制；③AMPK反馈调节线粒体稳态及BDNF表达的分子机制。本研究通过体内、外实验结合敲除及过表达技术揭示心衰时线粒体稳态失衡的新机制，为心衰防治提供新靶点。

线粒体稳态失衡是心衰时心肌能量代谢异常及功能障碍的重要原因，但其确切调节机制及新的干预靶点有待深入探讨，是本领域的重要科学问题。本项目围绕脑源性神经营养因子（BDNF）及其特异性酪氨酸激酶受体B（TrkB）对不同心衰模型中线粒体稳态的调节作用及分子机制开展了系列研究。分别建立压力负荷、慢性心肌缺血、抗肿瘤药物多柔比星三种心衰动物及细胞模型，发现激动BDNF/TrkB通路可显著改善心脏功能，抑制线粒体功能损伤，具体表现为促进线粒体生物合成，增强氧化磷酸化水平，抑制分裂融合失衡，最终改善心肌能量代谢，延缓心衰进程。同时，我们发现BDNF/TrkB通路调节心肌线粒体功能主要通过调控腺苷酸活化蛋白激酶（AMPK）和信号转导因子和转录激活因子3（STAT3）等关键信号分子发挥作用。本项目首次明确了BDNF/TrkB通路心肌线粒体保护作用，并揭示其维持心衰时线粒体稳态的分子机制，阐明了BDNF-TrkB-AMPK-STAT3通路可能是心衰防治的新靶点，评价了TrkB受体小分子激动剂7,8-DHF改善心衰的潜在作用。综上，本研究通过体内、外实验揭示了心衰时线粒体稳态失衡的新机制，为心衰防治提供新靶点。