发育过程中心肌细胞源性脑源性神经营养因子的缺失会导致成年小鼠心脏发生心肌变性和心力衰竭。
Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart.
作者信息
Li Lilin, Guo Hongyan, Lai Binglin, Liang Chunbao, Chen Hongyi, Chen Yilin, Guo Weimin, Yuan Ziqiang, Huang Ruijin, Zeng Zhaohua, Liang Liying, Zhao Hui, Zheng Xin, Li Yanmei, Pu Qin, Qi Xufeng, Cai Dongqing
机构信息
Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou, China.
Joint Laboratory for Regenerative Medicine, Chinese University of Hong Kong-Jinan University, Guangzhou, China.
出版信息
Front Cardiovasc Med. 2022 Aug 18;9:967463. doi: 10.3389/fcvm.2022.967463. eCollection 2022.
OBJECTIVE
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB-T1 were recently found to be expressed in cardiomyocytes. However, the functional role of cardiomyocyte-derived BDNF in heart pathophysiology is not yet fully known. Recent studies revealed that BDNF-TrkB pathway plays a critical role to maintain integrity of cardiac structure and function, cardiac pathology and regeneration of myocardial infarction (MI). Therefore, the BDNF-TrkB pathway may be a novel target for myocardial pathophysiology in the adult heart.
APPROACH AND RESULTS
In the present study, we established a cardiomyocyte-derived BDNF conditional knockout mouse in which BDNF expression in developing cardiomyocytes is ablated under the control of the Myosin heavy chain 6 (MYH6) promoter. The results of the present study show that ablation of cardiomyocyte-derived BDNF during development does not impair survival, growth or reproduction; however, in the young adult heart, it causes cardiomyocyte death, degeneration of the myocardium, cardiomyocyte hypertrophy, left atrial appendage thrombosis, decreased cardiac function, increased cardiac inflammation and ROS activity, and metabolic disorders, leading to heart failure (HF) in the adult heart and eventually resulting in a decrease in the one-year survival rate. In addition, ablation of cardiomyocyte-derived BDNF during the developmental stage leads to exacerbation of cardiac dysfunction and poor regeneration after MI in adult hearts.
CONCLUSION
Cardiomyocyte-derived BDNF is irreplaceable for maintaining the integrity of cardiac structure and function in the adult heart and regeneration after MI. Therefore, the BDNF-TrkB pathway will be a novel target for myocardial pathophysiology in the adult heart.
目的
脑源性神经营养因子（BDNF）及其受体TrkB-T1最近被发现可在心肌细胞中表达。然而，心肌细胞源性BDNF在心脏病理生理学中的功能作用尚未完全明确。最近的研究表明，BDNF-TrkB通路在维持心脏结构和功能的完整性、心脏病理学以及心肌梗死（MI）后的心肌再生中起着关键作用。因此，BDNF-TrkB通路可能是成年心脏心肌病理生理学的一个新靶点。
方法与结果
在本研究中，我们建立了一种心肌细胞源性BDNF条件性敲除小鼠，其中在肌球蛋白重链6（MYH6）启动子的控制下，发育中的心肌细胞中的BDNF表达被消除。本研究结果表明，发育过程中心肌细胞源性BDNF的缺失不会损害生存、生长或繁殖；然而，在年轻成年心脏中，它会导致心肌细胞死亡、心肌退化、心肌细胞肥大、左心耳血栓形成、心脏功能下降、心脏炎症和ROS活性增加以及代谢紊乱，导致成年心脏发生心力衰竭（HF），最终导致一年生存率降低。此外，发育阶段心肌细胞源性BDNF的缺失会导致成年心脏心肌梗死后心脏功能障碍加重和再生不良。
结论
心肌细胞源性BDNF对于维持成年心脏的心脏结构和功能完整性以及心肌梗死后的再生是不可替代的。因此，BDNF-TrkB通路将是成年心脏心肌病理生理学的一个新靶点。
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