Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1. Issue 2 (15th June 2022)

• Record Type: Journal Article
• Authors: Yang, Xue; Zhang, Manling; Xie, Bingxian; Peng, Zishan; Manning, Janet R; Zimmerman, Raymond; Wang, Qin; Wei, An-chi; Khalifa, Moustafa; Reynolds, Michael; Jin, Jenny; Om, Matthew; Zhu, Guangshuo; Bedja, Djahida; Jiang, Hong; Jurczak, Michael; Shiva, Sruti; Scott, Iain; O'Rourke, Brian; Kass, David A; Paolocci, Nazareno; Feng, Ning
• Is Part Of: Cardiovascular research. Volume 119:Issue 2(2023)
• Page Start: 571
• Page End: 586
• Publication Date: 2022-06-15
• Subjects: BDNF -- PGC-1α -- YY1 -- heart failure -- cardiac energetics; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac096
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. Methods and results: We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. Conclusion: Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response. Graphical Abstract: Graphical abstract