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Войти в исследования Frontiers in cell and developmental biology · 2026
Cardiomyocyte-derived BDNF restricts cardiac fibrosis by decreasing the activity of the TGF-β/Smad2/3 pathway and increasing Smad7 expression.
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Zhu Yu, Ran Yuanfei, Fu Tingting, Zheng Xin, Chen Yanjun, Liang Chunbao, Li Yanmei, Huang Ruijin, Zhao Hui, Pan Xiudi, Yuan Ziqiang, Pu Qin, Zeng Zhaohua, Feng Shanshan, Qi Xufeng, Lv Luocheng, Zhan Lixuan, Chen Yilin, Cai Dongqing
Аннотация
BACKGROUND AND OBJECTIVE: To investigate the role of cardiomyocyte-derived BDNF as an endogenous regulator to decrease cardiac fibrosis, its underlying mechanism and therapeutic potential.
METHODS: Single-nuclei RNA sequencing (snRNA-seq), KEGG, Gene Ontology and cell‒cell interaction analyses were performed to identify changes in cardiac cells, cardiac functions and pathways due to the conditional knockout of cardiomyocyte-derived BDNF (cardiomyocyte-BDNF-KO). Protein C-terminal sequencing, qPCR, WB, CCK8 assays, flow cytometry, BDNF-AAV9 treatment and histological staining were performed to investigate the roles of BDNF and the BDNF mimic 7,8-DHF (7,8-DHF) in cardiac fibroblasts cardiac myofibroblasts and cardiac fibrosis, and the cross-inhibition of the TGF-β and BDNF-TrkB-FL pathway.
RESULTS: snRNA-seq and bioinformatics analysis revealed that cardiomyocyte-BDNF-KO significantly increased the percentage of CFs, decreased the number of cardiomyocytes, and increased the activity of the TGF-β pathway in CFs. Functional studies confirmed that compared with those in wild-type hearts, the expression levels of key signaling molecules in the TGF-β pathway in cardiomyocyte-BDNF-KO CFs in the mouse heart were significantly higher. CFs and CMFs expressed the BDNF receptor TrkB-FL but not BDNF, and treatment with BDNF and 7,8-DHF decreased the expression of key signaling molecules in the TGF-β pathway in CFs and CMFs. BDNF inhibited CF and CMF proliferation, inhibited CF activation and transformation into CMFs, promoted CMF apoptosis, the accumulation of cells in S phase of the cell cycle and TrkB-FL phosphorylation in CFs and CMFs, increased Smad7 expression in CMFs, and inhibited the activity of the TGF-β/Smad2/3/α-SMA pathway. 7,8-DHF had the same effects as BDNF, as documented above. Furthermore, BDNF-AAV9 therapy for cardiomyocyte-BDNF-KO hearts increased Smad7 expression and decreased the activity of the TGF-β/Smad2/3 pathway and the expression of fibrotic effectors, which ameliorated cardiac fibrosis.
CONCLUSION: Cardiomyocyte-derived BDNF acts as an endogenous mediator to restrict cardiac fibrosis by inhibiting CF and CMF proliferation, CF activation and transformation into CMFs, and increasing arrest in S phase of the cell cycle in CFs and CMFs and the apoptosis of CMFs. The BDNF-TrkB-FL pathway cross-inhibits the activity of the TGF-β/Smad2/3/α-SMA pathway and increases the expression of Smad7. BDNF and 7,8-DHF have therapeutic potential for treating cardiac fibrosis.
METHODS: Single-nuclei RNA sequencing (snRNA-seq), KEGG, Gene Ontology and cell‒cell interaction analyses were performed to identify changes in cardiac cells, cardiac functions and pathways due to the conditional knockout of cardiomyocyte-derived BDNF (cardiomyocyte-BDNF-KO). Protein C-terminal sequencing, qPCR, WB, CCK8 assays, flow cytometry, BDNF-AAV9 treatment and histological staining were performed to investigate the roles of BDNF and the BDNF mimic 7,8-DHF (7,8-DHF) in cardiac fibroblasts cardiac myofibroblasts and cardiac fibrosis, and the cross-inhibition of the TGF-β and BDNF-TrkB-FL pathway.
RESULTS: snRNA-seq and bioinformatics analysis revealed that cardiomyocyte-BDNF-KO significantly increased the percentage of CFs, decreased the number of cardiomyocytes, and increased the activity of the TGF-β pathway in CFs. Functional studies confirmed that compared with those in wild-type hearts, the expression levels of key signaling molecules in the TGF-β pathway in cardiomyocyte-BDNF-KO CFs in the mouse heart were significantly higher. CFs and CMFs expressed the BDNF receptor TrkB-FL but not BDNF, and treatment with BDNF and 7,8-DHF decreased the expression of key signaling molecules in the TGF-β pathway in CFs and CMFs. BDNF inhibited CF and CMF proliferation, inhibited CF activation and transformation into CMFs, promoted CMF apoptosis, the accumulation of cells in S phase of the cell cycle and TrkB-FL phosphorylation in CFs and CMFs, increased Smad7 expression in CMFs, and inhibited the activity of the TGF-β/Smad2/3/α-SMA pathway. 7,8-DHF had the same effects as BDNF, as documented above. Furthermore, BDNF-AAV9 therapy for cardiomyocyte-BDNF-KO hearts increased Smad7 expression and decreased the activity of the TGF-β/Smad2/3 pathway and the expression of fibrotic effectors, which ameliorated cardiac fibrosis.
CONCLUSION: Cardiomyocyte-derived BDNF acts as an endogenous mediator to restrict cardiac fibrosis by inhibiting CF and CMF proliferation, CF activation and transformation into CMFs, and increasing arrest in S phase of the cell cycle in CFs and CMFs and the apoptosis of CMFs. The BDNF-TrkB-FL pathway cross-inhibits the activity of the TGF-β/Smad2/3/α-SMA pathway and increases the expression of Smad7. BDNF and 7,8-DHF have therapeutic potential for treating cardiac fibrosis.