Molecular Therapy: Nucleic Acids (Sep 2024)
Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling
- Merve Keles,
- Steve Grein,
- Natali Froese,
- Dagmar Wirth,
- Felix A. Trogisch,
- Rhys Wardman,
- Shruthi Hemanna,
- Nina Weinzierl,
- Philipp-Sebastian Koch,
- Stefanie Uhlig,
- Santosh Lomada,
- Gesine M. Dittrich,
- Malgorzata Szaroszyk,
- Ricarda Haustein,
- Jan Hegermann,
- Abel Martin-Garrido,
- Johann Bauersachs,
- Derk Frank,
- Norbert Frey,
- Karen Bieback,
- Julio Cordero,
- Gergana Dobreva,
- Thomas Wieland,
- Joerg Heineke
Affiliations
- Merve Keles
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; CFPM (Core Facility Platform Mannheim), Cardiac Imaging Center, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Steve Grein
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Natali Froese
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany
- Dagmar Wirth
- Helmholtz Center for Infection Research, Model Systems for Infection and Immunity, 38124 Braunschweig, Germany
- Felix A. Trogisch
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; CFPM (Core Facility Platform Mannheim), Cardiac Imaging Center, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Rhys Wardman
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Shruthi Hemanna
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Nina Weinzierl
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Philipp-Sebastian Koch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Stefanie Uhlig
- CFPM, FlowCore, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Santosh Lomada
- DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; ECAS, Department of Experimental Pharmacology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Gesine M. Dittrich
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Malgorzata Szaroszyk
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany
- Ricarda Haustein
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany
- Jan Hegermann
- Institute of Functional and Applied Anatomy, Core Unit Electron Microscopy, Hannover Medical School, 30625 Hannover, Germany
- Abel Martin-Garrido
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany
- Derk Frank
- Department of Internal Medicine III, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; DZHK, partner site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
- Norbert Frey
- DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Department of Internal Medicine III, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany
- Karen Bieback
- CFPM, FlowCore, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Julio Cordero
- ECAS, Department of Cardiovascular Genomics and Epigenomics, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Gergana Dobreva
- DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; ECAS, Department of Cardiovascular Genomics and Epigenomics, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Thomas Wieland
- DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; ECAS, Department of Experimental Pharmacology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany
- Joerg Heineke
- ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; CFPM (Core Facility Platform Mannheim), Cardiac Imaging Center, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany; DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Corresponding author: Joerg Heineke, European Center for Angioscience (ECAS), Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 7 – 11, 68167 Mannheim, Germany.
- Journal volume & issue
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Vol. 35,
no. 3
p. 102306
Abstract
Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.
