Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy
Abstract Background Takotsubo cardiomyopathy (TTC) is marked by an acute, transient, and reversible left ventricular systolic dysfunction triggered by stress, with endothelial dysfunction being one of its pathophysiological mechanisms. However, the precise molecular mechanism underlying the interact...
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BMC
2025-02-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04157-0 |
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| author | Xuehui Fan Guoqiang Yang Yinuo Wang Haojie Shi Katja Nitschke Katherine Sattler Mohammad Abumayyaleh Lukas Cyganek Philipp Nuhn Thomas Worst Bin Liao Gergana Dobreva Daniel Duerschmied Xiaobo Zhou Ibrahim El-Battrawy Ibrahim Akin |
| author_facet | Xuehui Fan Guoqiang Yang Yinuo Wang Haojie Shi Katja Nitschke Katherine Sattler Mohammad Abumayyaleh Lukas Cyganek Philipp Nuhn Thomas Worst Bin Liao Gergana Dobreva Daniel Duerschmied Xiaobo Zhou Ibrahim El-Battrawy Ibrahim Akin |
| author_sort | Xuehui Fan |
| collection | DOAJ |
| description | Abstract Background Takotsubo cardiomyopathy (TTC) is marked by an acute, transient, and reversible left ventricular systolic dysfunction triggered by stress, with endothelial dysfunction being one of its pathophysiological mechanisms. However, the precise molecular mechanism underlying the interaction between endothelial cells and cardiomyocytes during TTC remains unclear. This study reveals that exosomal miRNAs derived from endothelial cells exposed to catecholamine contribute to ion channel dysfunction in the setting of TTC. Methods Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with epinephrine (Epi) or exosomes (Exo) from Epi-treated human cardiac microvascular endothelial cells (HCMECs) or Exo derived from HCMECs transfected with miR-126-3p. The immunofluorescence staining, flow cytometry, qPCR, single-cell contraction, intracellular calcium transients, patch-clamp, dual luciferase reporter assay and western blot were performed for the study. Results Modeling TTC with high doses of epinephrine (Epi) treatment in hiPSC-CMs shows suppression of depolarization velocity (Vmax), prolongation of action potential duration (APD), and induction of arrhythmic events. Exo derived from HCMECs treated with Epi (Epi-exo) mimicked or enhanced the effects of Epi. Epi exposure led to elevated levels of miR-126-3p in both HCMECs and their exosomes. Exo enriched with miR-126-3p demonstrated similar effects as Epi-exo, establishing the crucial role of miR-126-3p in the mechanism of Epi-exo. Dual luciferase reporter assay coupled with gene mutation techniques identified that miR-126-3p was found to target the regulator of G-protein signaling 3 (RGS3) gene. Western blot and qPCR analyses confirmed that miR-126-3p-mimic reduced RGS3 expression in both HCMECs and hiPSC-CMs, indicating miR-126-3p inhibits RGS3 signaling. Additionally, miR-126-3p levels were significantly higher in the serum of TTC patients compared to healthy controls and patients who had recovered from TTC. Conclusions Our study is the first to reveal that exosomal miR-126-3p, originating from endothelial cells, contributes to ion channel dysfunction by regulating RGS3 signaling in cardiomyocytes. These findings provide new perspectives on the pathogenesis of TTC and suggest potential therapeutic targets for treatment. Graphical Abstract |
| format | Article |
| id | doaj-art-d54faca5173044e0a99abfa7016e88c5 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-02-01 |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-d54faca5173044e0a99abfa7016e88c52025-02-09T12:15:36ZengBMCStem Cell Research & Therapy1757-65122025-02-0116112110.1186/s13287-025-04157-0Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathyXuehui Fan0Guoqiang Yang1Yinuo Wang2Haojie Shi3Katja Nitschke4Katherine Sattler5Mohammad Abumayyaleh6Lukas Cyganek7Philipp Nuhn8Thomas Worst9Bin Liao10Gergana Dobreva11Daniel Duerschmied12Xiaobo Zhou13Ibrahim El-Battrawy14Ibrahim Akin15Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityDepartment of Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg UniversityDepartment of Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg UniversityDepartment of Urology and Urosurgery, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityStem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center GöttingenDepartment of Urology and Urosurgery, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Urology and Urosurgery, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Cardiac Macrovascular Surgery, Affiliated Hospital of Southwest Medical UniversityDepartment of Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg UniversityDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityDepartment of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of BochumDepartment of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg UniversityAbstract Background Takotsubo cardiomyopathy (TTC) is marked by an acute, transient, and reversible left ventricular systolic dysfunction triggered by stress, with endothelial dysfunction being one of its pathophysiological mechanisms. However, the precise molecular mechanism underlying the interaction between endothelial cells and cardiomyocytes during TTC remains unclear. This study reveals that exosomal miRNAs derived from endothelial cells exposed to catecholamine contribute to ion channel dysfunction in the setting of TTC. Methods Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with epinephrine (Epi) or exosomes (Exo) from Epi-treated human cardiac microvascular endothelial cells (HCMECs) or Exo derived from HCMECs transfected with miR-126-3p. The immunofluorescence staining, flow cytometry, qPCR, single-cell contraction, intracellular calcium transients, patch-clamp, dual luciferase reporter assay and western blot were performed for the study. Results Modeling TTC with high doses of epinephrine (Epi) treatment in hiPSC-CMs shows suppression of depolarization velocity (Vmax), prolongation of action potential duration (APD), and induction of arrhythmic events. Exo derived from HCMECs treated with Epi (Epi-exo) mimicked or enhanced the effects of Epi. Epi exposure led to elevated levels of miR-126-3p in both HCMECs and their exosomes. Exo enriched with miR-126-3p demonstrated similar effects as Epi-exo, establishing the crucial role of miR-126-3p in the mechanism of Epi-exo. Dual luciferase reporter assay coupled with gene mutation techniques identified that miR-126-3p was found to target the regulator of G-protein signaling 3 (RGS3) gene. Western blot and qPCR analyses confirmed that miR-126-3p-mimic reduced RGS3 expression in both HCMECs and hiPSC-CMs, indicating miR-126-3p inhibits RGS3 signaling. Additionally, miR-126-3p levels were significantly higher in the serum of TTC patients compared to healthy controls and patients who had recovered from TTC. Conclusions Our study is the first to reveal that exosomal miR-126-3p, originating from endothelial cells, contributes to ion channel dysfunction by regulating RGS3 signaling in cardiomyocytes. These findings provide new perspectives on the pathogenesis of TTC and suggest potential therapeutic targets for treatment. Graphical Abstracthttps://doi.org/10.1186/s13287-025-04157-0Takotsubo cardiomyopathyCatecholamine excessExosomesmiRNA-126-3pHuman-induced pluripotent stem cell-derived cardiomyocytes |
| spellingShingle | Xuehui Fan Guoqiang Yang Yinuo Wang Haojie Shi Katja Nitschke Katherine Sattler Mohammad Abumayyaleh Lukas Cyganek Philipp Nuhn Thomas Worst Bin Liao Gergana Dobreva Daniel Duerschmied Xiaobo Zhou Ibrahim El-Battrawy Ibrahim Akin Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy Stem Cell Research & Therapy Takotsubo cardiomyopathy Catecholamine excess Exosomes miRNA-126-3p Human-induced pluripotent stem cell-derived cardiomyocytes |
| title | Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy |
| title_full | Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy |
| title_fullStr | Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy |
| title_full_unstemmed | Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy |
| title_short | Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy |
| title_sort | exosomal mir 126 3p derived from endothelial cells induces ion channel dysfunction by targeting rgs3 signaling in cardiomyocytes a novel mechanism in takotsubo cardiomyopathy |
| topic | Takotsubo cardiomyopathy Catecholamine excess Exosomes miRNA-126-3p Human-induced pluripotent stem cell-derived cardiomyocytes |
| url | https://doi.org/10.1186/s13287-025-04157-0 |
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