Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart

Lilin Li; Hongyan Guo; Binglin Lai; Chunbao Liang; Hongyi Chen; Yilin Chen; Weimin Guo; Ziqiang Yuan; Ruijin Huang; Zhaohua Zeng; Liying Liang; Hui Zhao; Xin Zheng; Yanmei Li; Qin Pu; Xufeng Qi; Dongqing Cai

doi:10.3389/fcvm.2022.967463

Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart

Front Cardiovasc Med. 2022 Aug 18:9:967463. doi: 10.3389/fcvm.2022.967463. eCollection 2022.

Authors

Lilin Li^{1

2

3

4}, Hongyan Guo^{1

2

3

4

5}, Binglin Lai^{1

2

3

4}, Chunbao Liang^{1

2

3

4}, Hongyi Chen^{1

2

3

4}, Yilin Chen^{1

2

3

4}, Weimin Guo^{1

2

3

4}, Ziqiang Yuan⁶, Ruijin Huang^{7

8}, Zhaohua Zeng⁹, Liying Liang⁹, Hui Zhao¹⁰, Xin Zheng^{1

2

3

4}, Yanmei Li^{1

2

3

4}, Qin Pu⁷, Xufeng Qi^{1

2

3

4}, Dongqing Cai^{1

2

3

4}

Affiliations

¹ Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou, China.
² Joint Laboratory for Regenerative Medicine, Chinese University of Hong Kong-Jinan University, Guangzhou, China.
³ International Base of Collaboration for Science and Technology (JNU), The Ministry of Science and Technology and Guangdong Province, Guangzhou, China.
⁴ Department of Developmental and Regenerative Biology, Jinan University, Guangzhou, China.
⁵ Jiangxi Provincial Key Laboratory of Medical Immunology and Immunotherapy, Jiangxi Academy of Medical Sciences, Nanchang, China.
⁶ Department of Medical Oncology, Robert Wood Johnson of Medical School, Cancer Institute of New Jersey, New Brunswick, NJ, United States.
⁷ Department of Neuroanatomy, Institute of Anatomy, University of Bonn, Bonn, Germany.
⁸ Department of Anatomy and Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany.
⁹ Division of Cardiology, Department of Internal Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹⁰ Stem Cell and Regeneration TRP, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Abstract

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.

Keywords: cardiomyocyte; cardiomyocyte-derived BDNF conditional knockout; degeneration of the myocardium; heart failure; myocardial infarction.