Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction
Introduction: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. Objective: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of...
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Elsevier
2025-02-01
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| author | Guoxing Li Huilin Zhao Zhe Cheng Junjin Liu Gang Li Yongzheng Guo |
| author_facet | Guoxing Li Huilin Zhao Zhe Cheng Junjin Liu Gang Li Yongzheng Guo |
| author_sort | Guoxing Li |
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| description | Introduction: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. Objective: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. Methods: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. Results: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. Conclusion: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality. |
| format | Article |
| id | doaj-art-ca2055fbaa5143a5bf471397deb58ada |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Journal of Advanced Research |
| spelling | doaj-art-ca2055fbaa5143a5bf471397deb58ada2025-01-18T05:04:17ZengElsevierJournal of Advanced Research2090-12322025-02-0168215230Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fractionGuoxing Li0Huilin Zhao1Zhe Cheng2Junjin Liu3Gang Li4Yongzheng Guo5Institute of Life Sciences, Chongqing Medical University, 400016, ChinaInstitute of Life Sciences, Chongqing Medical University, 400016, ChinaDepartment of Cardiology, Chongqing University Three Gorges Hospital, Chongqing 404199, ChinaDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, ChinaInstitute of Life Sciences, Chongqing Medical University, 400016, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, 400016, China; Corresponding authors.Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Corresponding authors.Introduction: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. Objective: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. Methods: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. Results: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. Conclusion: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.http://www.sciencedirect.com/science/article/pii/S2090123224000687HFpEFscRNA-seqANGPTL4MetabolismAngiogenesis |
| spellingShingle | Guoxing Li Huilin Zhao Zhe Cheng Junjin Liu Gang Li Yongzheng Guo Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction Journal of Advanced Research HFpEF scRNA-seq ANGPTL4 Metabolism Angiogenesis |
| title | Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| title_full | Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| title_fullStr | Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| title_full_unstemmed | Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| title_short | Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| title_sort | single cell transcriptomic profiling of heart reveals angptl4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction |
| topic | HFpEF scRNA-seq ANGPTL4 Metabolism Angiogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224000687 |
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