Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling
Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed <i>Gadlor1</i> and <i>Gadlor2</i>, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of <i>Gadlor1</i> and <i>Gadlor2</i> aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound <i>Gadlor1/2</i> knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, <i>Gadlor1/2</i> KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. <i>Gadlor1</i> and <i>Gadlor2</i>, 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 <i>Gadlor</i> 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.
Authors
- Felix A. Trogisch (ORCID: https://orcid.org/0000-0002-3513-4362)
- Natali Froese
- Derk Frank (ORCID: https://orcid.org/0000-0001-7561-075X)
- Malgorzata Szaroszyk (ORCID: https://orcid.org/0009-0008-4051-3958)
- Norbert Frey (ORCID: https://orcid.org/0000-0001-7611-378X)
- Rhys Wardman (ORCID: https://orcid.org/0000-0003-3128-6278)
- Merve Keleş (ORCID: https://orcid.org/0000-0002-5212-3753)
- Philipp‐Sebastian Koch (ORCID: https://orcid.org/0000-0001-5236-0516)
- Johann Bauersachs (ORCID: https://orcid.org/0000-0002-9341-117X)
- Ricarda Haustein
- Abel Martín-Garrido
- Gesine M. Dittrich (ORCID: https://orcid.org/0000-0002-9053-078X)
- Steve Grein (ORCID: https://orcid.org/0000-0002-4095-7830)
- Karen Bieback (ORCID: https://orcid.org/0000-0003-2621-0703)
- Joerg Heineke (ORCID: https://orcid.org/0000-0002-1541-3030)
- Gergana D. Dobreva (ORCID: https://orcid.org/0000-0002-4814-9416)
- Nina Weinzierl
- Shruthi Hemanna (ORCID: https://orcid.org/0000-0001-7934-2801)
- Stefanie Uhlig
- Thomas Wieland (ORCID: https://orcid.org/0000-0001-8262-8261)
- Dagmar Wirth (ORCID: https://orcid.org/0000-0002-2541-6251)
- Santosh Lomada
- Julio Cordero (ORCID: https://orcid.org/0000-0002-2136-1783)
- Jan Hegermann (ORCID: https://orcid.org/0000-0001-7893-8507)
Institutions
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Medizinische Hochschule Hannover (DE)
- University Hospital Schleswig-Holstein (DE)
- Helmholtz Centre for Infection Research (DE)
- German Centre for Cardiovascular Research (DE)
- University Medical Centre Mannheim (DE)
- Clinical Research Center Kiel (DE)
- Epigenomics (Germany) (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Molecular Therapy — Nucleic Acids
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1016/j.omtn.2024.102306
- Citations
- 3
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 0.86
Funders
- Deutsche Forschungsgemeinschaft