Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy.

Daniel Duerschmied, Guoqiang Yang, Katherine Sattler, Philipp Nuhn, Xuehui Fan, Bin Liao, Xiaobo Zhou, Lukas Cyganek, Ibrahim El-Battrawy, Mohammad Abumayyaleh, Ibrahim Akin, Yinuo Wang, Haojie Shi, Katja Nitschke, Thomas Worst, Gergana Dobreva

Journal: Stem cell research & therapy 2025;16(1):36

PMID: 39901299

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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.

Address: Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Mannheim, Germany. [email protected].; Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China. [email protected].; Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China. [email protected].; European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim, Mannheim, Germany. [email protected].; Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Mannheim, Germany.; Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.; Department of Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Department of Urology and Urosurgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Mannheim, Germany.; European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim, Mannheim, Germany.; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site, Göttingen, Germany.; Department of Cardiac Macrovascular Surgery, Affiliated Hospital of Southwest Medical University, Sichuan, 646000, China.; Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Mannheim, Germany. [email protected].; Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China. [email protected].; European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim, Mannheim, Germany. [email protected].; Department of Cardiac Macrovascular Surgery, Affiliated Hospital of Southwest Medical University, Sichuan, 646000, China. [email protected].; Department of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, 44789, Bochum, Germany.; Institute of Physiology, Department of Cellular and Translational Physiology, Medical Faculty and Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.

DOI: 10.1186/s13287-025-04157-0

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MeSH Terms: MicroRNAs, Humans, Myocytes, Cardiac, Exosomes, Takotsubo Cardiomyopathy, Signal Transduction, Endothelial Cells, Induced Pluripotent Stem Cells, RGS Proteins, Epinephrine, Ion Channels