Endothelial cell-derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate pathological cardiac remodeling via intercellular crosstalk
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Abstract Background Pathological overload triggers maladaptive myocardial remodeling that leads to heart failure. Recent studies have shown that long non-coding RNAs (lncRNAs) regulate cardiac remodeling. This study investigates two recently discovered, secreted lncRNAs, Gadlor1 and Gadlor2 ( Gadlor 1/2 ). Methods We generated compound Gadlor 1/2 knock-out (KO) mice and compared their response to pressure overload by transverse aortic constriction (TAC) to that of wild-type (WT) littermates. Endothelial cells, fibroblasts and cardiomyocytes were isolated from the hearts of both genotypes after TAC and their transcriptome was investigated by RNA sequencing. Gadlor target proteins were identified by RNA antisense purification coupled with mass spectrometry (RAP-MS) in cardiomyocytes. In addition, we investigated the effects of cardiac overexpression of Gadlor1 / 2 . Results Gadlor1/2 are jointly upregulated in failing mouse hearts as well as in the myocardium of heart failure patients. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 KO mice, in turn, exerted markedly reduced myocardial hypertrophy, fibrosis and dysfunction, but more angiogenesis during short and long-standing 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, induce pro-hypertrophic gene-expression and enhance calcium re-uptake into the sarcoplasmic reticulum. Conclusion Gadlor1 and Gadlor2 are lncRNAs that are mainly enriched in EC-derived EVs and are jointly upregulated in mouse and human hearts during pathological overload. We reveal a crucial endothelial cell-cardiomyocyte crosstalk, which aims at restoring calcium homeostasis in cardiomyocytes during overload at the cost of aggravated hypertrophy and fibrosis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Endothelial cell-derived, secreted long non-coding RNAs <i>Gadlor1</i> and <i>Gadlor2</i> aggravate pathological cardiac remodeling via intercellular crosstalk
- Date Crossref
- 19/09/2022
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Heidelberg University Cardiac Imaging Center pays non établi dans la noticeUniversité ou école supérieure
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University Hospital Heidelberg pays non établi dans la noticeÉtablissement de santé
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German Centre for Cardiovascular Research pays non établi dans la noticeStructure de recherche
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University Medical Centre Mannheim pays non établi dans la noticeOrganisme public
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Medizinische Hochschule Hannover pays non établi dans la noticeUniversité ou école supérieure
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Helmholtz Centre for Infection Research pays non établi dans la noticeStructure de recherche
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University Hospital Schleswig-Holstein Department of Internal Medicine III pays non établi dans la noticeÉtablissement de santé
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University of Lübeck pays non établi dans la noticeUniversité ou école supérieure
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Epigenomics (Germany) pays non établi dans la noticeEntreprise
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DZHK (German Center for Cardiovascular Research) pays non établi dans la noticeInstitution
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Department of Cardiology and Angiology pays non établi dans la noticeInstitution
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University Medical Center and Medical Faculty Mannheim Department of Dermatology pays non établi dans la noticeUniversité ou école supérieure
Cardiac Imaging Center — Heidelberg University, University Hospital Heidelberg et German Centre for Cardiovascular Research, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.