Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart.
Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart.
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DOI：
10.3389/fcvm.2022.967463
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发表时间：
2022
影响因子：
3.6
通讯作者：
Cai, Dongqing
中科院分区：
文献类型：
--
作者：
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
关键词：
脑源性神经营养因子（BDNF）及其受体TrkB-T1最近被发现在心肌细胞中表达。然而，心肌细胞源性BDNF在心脏病理生理学中的功能作用尚不完全清楚。近年来研究发现，BDNF-TrkB通路在维持心脏结构和功能的完整性、心脏病理和心肌梗死（MI）后的再生中起着重要作用。因此，BDNF-TrkB通路可能是成人心脏心肌病理生理学的新靶点。在本研究中，我们建立了一个心肌细胞衍生的BDNF条件性基因敲除小鼠，其中BDNF在发育中的心肌细胞中的表达在肌球蛋白重链6（MYH 6）启动子的控制下被消融。本研究的结果表明，在发育过程中去除心肌细胞源性BDNF不会损害存活、生长或繁殖;然而，在年轻成人心脏中，它引起心肌细胞死亡、心肌变性、心肌细胞肥大、左心房附件血栓形成、心脏功能下降、心脏炎症和ROS活性增加，以及代谢紊乱，导致成人心脏的心力衰竭（HF）并最终导致一年存活率的降低。此外，在发育阶段消融心肌细胞源性BDNF导致成年心脏MI后心功能障碍加重和再生不良。心肌细胞源性BDNF在维持成年心脏结构和功能的完整性以及心肌梗死后的再生方面具有不可替代的作用。因此，BDNF-TrkB通路将成为成人心脏心肌病理生理学的新靶点。
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. 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. 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.
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