FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice
Abstract Fibronectin type III domain-containing (FNDC) proteins play critical roles in cellular homeostasis and cardiac injury, and our recent findings define FNDC5 as a promising cardioprotectant against doxorubicin- and aging-related cardiac injury. FNDC4 displays a high homology with FNDC5; howev...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53564-z |
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| author | Xin Zhang Yi-Peng Gao Wen-Sheng Dong Kang Li Yu-Xin Hu Yun-Jia Ye Can Hu |
| author_facet | Xin Zhang Yi-Peng Gao Wen-Sheng Dong Kang Li Yu-Xin Hu Yun-Jia Ye Can Hu |
| author_sort | Xin Zhang |
| collection | DOAJ |
| description | Abstract Fibronectin type III domain-containing (FNDC) proteins play critical roles in cellular homeostasis and cardiac injury, and our recent findings define FNDC5 as a promising cardioprotectant against doxorubicin- and aging-related cardiac injury. FNDC4 displays a high homology with FNDC5; however, its role and mechanism in cardiac ischemia/reperfusion (I/R) injury remain elusive. Here, we show that cardiac and plasma FNDC4 levels are elevated during I/R injury in a hypoxia-inducible factor 1α (HIF1α)-dependent manner. Cardiac-specific FNDC4 overexpression facilitates, while cardiac-specific FNDC4 knockdown inhibits cardiomyocyte survival and angiogenesis in I/R-stressed hearts of male mice through regulating the proteasomal degradation of HIF1α. Interestingly, FNDC4 does not directly stimulate angiogenesis of endothelial cells, but increases the expression and secretion of fibroblast growth factor 1 from cardiomyocytes to enhance angiogenesis in a paracrine manner. Moreover, therapeutic administration of recombinant FNDC4 protein is sufficient to alleviate cardiac I/R injury in male mice, without resulting in significant side effects. In this work, we reveal that FNDC4 alleviates cardiac I/R injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis, and define FNDC4 as a promising predictive and therapeutic target of cardiac I/R injury. |
| format | Article |
| id | doaj-art-4f9a6b2a4e5d4838b712d6ca73f7e388 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-4f9a6b2a4e5d4838b712d6ca73f7e3882024-11-10T12:33:35ZengNature PortfolioNature Communications2041-17232024-11-0115111710.1038/s41467-024-53564-zFNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male miceXin Zhang0Yi-Peng Gao1Wen-Sheng Dong2Kang Li3Yu-Xin Hu4Yun-Jia Ye5Can Hu6Department of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic DiseasesDepartment of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Research Center for Medical Imaging in Hubei Province, Hubei Province Key Laboratory of Molecular ImagingAbstract Fibronectin type III domain-containing (FNDC) proteins play critical roles in cellular homeostasis and cardiac injury, and our recent findings define FNDC5 as a promising cardioprotectant against doxorubicin- and aging-related cardiac injury. FNDC4 displays a high homology with FNDC5; however, its role and mechanism in cardiac ischemia/reperfusion (I/R) injury remain elusive. Here, we show that cardiac and plasma FNDC4 levels are elevated during I/R injury in a hypoxia-inducible factor 1α (HIF1α)-dependent manner. Cardiac-specific FNDC4 overexpression facilitates, while cardiac-specific FNDC4 knockdown inhibits cardiomyocyte survival and angiogenesis in I/R-stressed hearts of male mice through regulating the proteasomal degradation of HIF1α. Interestingly, FNDC4 does not directly stimulate angiogenesis of endothelial cells, but increases the expression and secretion of fibroblast growth factor 1 from cardiomyocytes to enhance angiogenesis in a paracrine manner. Moreover, therapeutic administration of recombinant FNDC4 protein is sufficient to alleviate cardiac I/R injury in male mice, without resulting in significant side effects. In this work, we reveal that FNDC4 alleviates cardiac I/R injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis, and define FNDC4 as a promising predictive and therapeutic target of cardiac I/R injury.https://doi.org/10.1038/s41467-024-53564-z |
| spellingShingle | Xin Zhang Yi-Peng Gao Wen-Sheng Dong Kang Li Yu-Xin Hu Yun-Jia Ye Can Hu FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice Nature Communications |
| title | FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice |
| title_full | FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice |
| title_fullStr | FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice |
| title_full_unstemmed | FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice |
| title_short | FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice |
| title_sort | fndc4 alleviates cardiac ischemia reperfusion injury through facilitating hif1α dependent cardiomyocyte survival and angiogenesis in male mice |
| url | https://doi.org/10.1038/s41467-024-53564-z |
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