Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction
Abstract Sodium-glucose co-transport protein 2 (SGLT2) inhibitors, a novel category of oral hypoglycemic agents, offer a promising outlook for individuals experiencing heart failure with reduced ejection fraction. Evidence is emerging that highlights their potential in alleviating myocardial fibrosi...
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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41598-024-80829-w |
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| author | Hong-xia Ma Ke Wu Fei-hong Dong Bing-kun Cai Di Wu Hui-yi Lu |
| author_facet | Hong-xia Ma Ke Wu Fei-hong Dong Bing-kun Cai Di Wu Hui-yi Lu |
| author_sort | Hong-xia Ma |
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| description | Abstract Sodium-glucose co-transport protein 2 (SGLT2) inhibitors, a novel category of oral hypoglycemic agents, offer a promising outlook for individuals experiencing heart failure with reduced ejection fraction. Evidence is emerging that highlights their potential in alleviating myocardial fibrosis and oxidative stress. However, the precise mechanisms through which SGLT2 inhibitors influence myocardial fibrosis induced by angiotensin II (Ang II) or transforming growth factor-β1 (TGF-β1) are not fully understood. This study aims to explore the intricate mechanisms by which SGLT2 inhibitors ameliorate myocardial fibrosis, particularly focusing on the nuanced interplay within the SIRT6 signaling pathway. Primary cardiac fibroblasts were isolated from the hearts of 1-3-day-old neonatal KM mice, were stimulated with Ang II or TGF-β1 to establish an in vitro model of myocardial fibrosis. Treatment with 10 µM Empagliflozin (EMPA) and Dapagliflozin (DAPA) significantly curtailed the proliferation of cardiac fibroblasts, substantially reduced collagen expression induced by Ang II/TGF-β1, and mitigated the phenotypic transformation and oxidative stress response. SIRT6, which is closely associated with myocardial fibrosis, demonstrated that the suppression its expression attenuated the protective effects of EMPA and DAPA against myocardial fibrosis and oxidative stress. Our findings suggest that SGLT2 inhibitors markedly decrease the Ang II/TGF-β1-induced transformation of cardiac fibroblasts to a myofibroblast phenotype by upregulating SIRT6 protein expression, thereby inhibiting oxidative stress and ameliorating myocardial fibrosis. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-10874d3aa9434402a61d8902c6fb53c42024-12-29T12:31:18ZengNature PortfolioScientific Reports2045-23222024-12-0114111310.1038/s41598-024-80829-wEffects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reductionHong-xia Ma0Ke Wu1Fei-hong Dong2Bing-kun Cai3Di Wu4Hui-yi Lu5Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, The Second Affiliated Hospital of Dalian Medical UniversityAbstract Sodium-glucose co-transport protein 2 (SGLT2) inhibitors, a novel category of oral hypoglycemic agents, offer a promising outlook for individuals experiencing heart failure with reduced ejection fraction. Evidence is emerging that highlights their potential in alleviating myocardial fibrosis and oxidative stress. However, the precise mechanisms through which SGLT2 inhibitors influence myocardial fibrosis induced by angiotensin II (Ang II) or transforming growth factor-β1 (TGF-β1) are not fully understood. This study aims to explore the intricate mechanisms by which SGLT2 inhibitors ameliorate myocardial fibrosis, particularly focusing on the nuanced interplay within the SIRT6 signaling pathway. Primary cardiac fibroblasts were isolated from the hearts of 1-3-day-old neonatal KM mice, were stimulated with Ang II or TGF-β1 to establish an in vitro model of myocardial fibrosis. Treatment with 10 µM Empagliflozin (EMPA) and Dapagliflozin (DAPA) significantly curtailed the proliferation of cardiac fibroblasts, substantially reduced collagen expression induced by Ang II/TGF-β1, and mitigated the phenotypic transformation and oxidative stress response. SIRT6, which is closely associated with myocardial fibrosis, demonstrated that the suppression its expression attenuated the protective effects of EMPA and DAPA against myocardial fibrosis and oxidative stress. Our findings suggest that SGLT2 inhibitors markedly decrease the Ang II/TGF-β1-induced transformation of cardiac fibroblasts to a myofibroblast phenotype by upregulating SIRT6 protein expression, thereby inhibiting oxidative stress and ameliorating myocardial fibrosis.https://doi.org/10.1038/s41598-024-80829-wMyocardial fibrosisEmpagliflozinDapagliflozinOxidative stress injurySIRT6 |
| spellingShingle | Hong-xia Ma Ke Wu Fei-hong Dong Bing-kun Cai Di Wu Hui-yi Lu Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction Scientific Reports Myocardial fibrosis Empagliflozin Dapagliflozin Oxidative stress injury SIRT6 |
| title | Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction |
| title_full | Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction |
| title_fullStr | Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction |
| title_full_unstemmed | Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction |
| title_short | Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction |
| title_sort | effects of empagliflozin and dapagliflozin in alleviating cardiac fibrosis through sirt6 mediated oxidative stress reduction |
| topic | Myocardial fibrosis Empagliflozin Dapagliflozin Oxidative stress injury SIRT6 |
| url | https://doi.org/10.1038/s41598-024-80829-w |
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