<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload"^^ . "Background: Pathological cardiac overload triggers maladaptive myocardial remodelling that \r\npredisposes to the development of heart failure. The contribution of long non-coding RNAs \r\n(lncRNAs) to intercellular signalling during cardiac remodelling is largely unknown. In this study, \r\ntwo novel lncRNAs, Gadlor1 and Gadlor2, which are enriched in endothelial-cell-derived \r\nextracellular vesicles (EVs) were described. The functional role of endogenous Gadlor lncRNAs \r\nwas investigated in intra-cardiac communication during cardiac remodelling upon pressure \r\noverload.\r\nMethods and Results: Analysis of the different cardiac cell types revealed that Gadlor1 and\r\nGadlor2 expression were enriched in endothelial cells (EC) compared to fibroblast (FB) and \r\ncardiomyocytes (CM). Interestingly, the abundance of Gadlor lncRNAs was even more \r\npronounced in EC-derived EVs, suggesting a potential role in paracrine signalling. The effect \r\nof Gadlor knock-out (Gadlor-KO) and Gadlor overexpression during cardiac pressure overload \r\ninduced by transverse aortic constriction (TAC) was analysed by echocardiography, histological \r\nanalyses and bulk RNA sequencing from isolated cardiac cells.\r\nGadlor1 and Gadlor2 are upregulated in failing mouse hearts as well as in the myocardium and \r\nserum of hypertrophy patients. Interestingly, secreted Gadlor lncRNAs from ECs were mainly \r\ntaken up by CM, and to a lesser extent by cardiac FBs. Gadlor-KO mice exhibited reduced \r\ncardiomyocyte hypertrophy, diminished myocardial fibrosis and improved cardiac function, but\r\nparadoxically, suffered from sudden death during prolonged pressure overload.\r\nGadlor overexpression, in turn, triggered hypertrophy, fibrosis and cardiac dysfunction.\r\nMechanistically, Gadlor1 and Gadlor2 inhibited angiogenic gene expression in ECs, while \r\npromoting the expression of pro-fibrotic genes in cardiac FBs. In CMs, Gadlor1 and \r\nGadlor2 upregulate mitochondrial and pro-hypertrophic genes, but downregulate angiogenesis\r\nand inflammatory genes.\r\nGLYR1 and CaMKII were identified as Gadlor1/2 interaction partners by RNA antisense \r\npurification coupled with mass-spectrometry (RAP-MS). These binding partners could in part \r\n8\r\nexplain the changes observed in gene expression of Gadlor-KO CMs, cardiomyocyte hypertrophy \r\nand perturbed calcium dynamics, respectively. Phosphorylation of phospholamban (p-PLN) by \r\nCaMKII at threonine-17 alters the activity of the SERCA pump and therefore calcium reuptake into \r\nthe sarcoplasmic reticulum. A significant decrease in pThr17-PLN in Gadlor-KO heart tissue \r\nsamples, and a considerable increase in pThr17-PLN in Gadlor1/2 overexpressing heart tissue \r\nsamples compared to WT after 2 weeks of TAC suggested that Gadlor lncRNAs promote CaMKII \r\nactivity. Indeed, reduced or increased CaMKII activation could explain in large parts ameliorated \r\nor exaggerated maladaptive remodelling during Gadlor knock-out or overexpression, \r\nrespectively.\r\nConclusions: Gadlor1 and Gadlor2 are novel lncRNAs, which are upregulated in cardiac \r\npathological overload and are secreted from endothelial cells within EVs. Gadlor1 and \r\nGadlor2 induce cardiac dysfunction, cardiomyocyte hypertrophy and myocardial fibrosis by acting \r\non multiple cardiac cells, affecting cellular gene expression and by affecting calcium dynamics in \r\ncardiomyocytes, which take up the Gadlor1/2 by EV-mediated transfer from endothelial cells. \r\nTargeted inhibition of Gadlor lncRNAs in endothelial cells or fibroblasts might serve as a \r\ntherapeutic strategy in the future."^^ . "2023" . . . . . . . "Merve"^^ . "Keles"^^ . "Merve Keles"^^ . . . . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (PDF)"^^ . . . "PhD Dissertation_MerveKeles_Final.pdf"^^ . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Secreted long non-coding RNAs Gadlor1 and \r\nGadlor2 act as mediators of cardiac remodelling \r\nduring pressure overload (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #32910 \n\nSecreted long non-coding RNAs Gadlor1 and \nGadlor2 act as mediators of cardiac remodelling \nduring pressure overload\n\n" . "text/html" . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .