Deletion of long non-coding RNAs Gadlor1 and Gadlor2 preserves cardiac function during pressure overload

Studies have shown a crucial role of lncRNAs in cardiac function and disease. Recently, we have identified two lncRNAs named Gadlor1 and Gadlor2, which are enriched in non-myocyte derived extracellular vesicles(EVs). We aim to investigate the functional effects and molecular mechanisms of secreted Gadlors in cardiac remodelling. Expression of GADLORs was elevated in the myocardium and serum of heart failure patients. Postnatal analysis in different organs of wild-type (WT) mice showed a stable expression in the brain, while their expression increased in the heart and liver towards adulthood. Cellular expression analysis in the heart showed the highest Gadlor expression in endothelial cells (ECs) followed by fibroblasts (FBs) and cardiomyocytes with the lowest expression levels. Interestingly, Gadlor abundance was strongly enriched in EVs derived from ECs and FBs, respectively. To determine the impact of endogenous Gadlors, mice with systemic knock-out of Gadlors (KO) were generated. Unchallenged KO mice were indistinguishable from WT littermates based on appearance, body weight, heart weight, and baseline echocardiographic analysis. We next investigated whether Gadlor-KO affects the response to cardiac pressure overload. After transverse aortic constriction(TAC), deletion of Gadlors markedly ameliorated cardiac hypertrophy as shown by a reduced increase in cardiomyocyte area and hypertrophy-associated genes. Additionally, Gadlor-KO mice exerted less TAC-induced cardiac dysfunction and loss of compliance and were protected from heart failure-induced lung congestion. Moreover, myocardial capillarization during pressure overload was substantially increased in KO mice after TAC compared to WT mice. Interestingly, KO mice were strongly protected from extracellular matrix deposition, and exerted significantly less induction of both collagen I and III at mRNA level, indicating a massively improved fibrotic response and a preserved endothelial function. RNA sequencing of cardiac tissue after TAC confirmed the downregulation of matrix genes in KO mice and revealed a significant upregulation of fatty-acid metabolism-related genes compared to WT mice. Investigations to decipher the mechanism of action of Gadlors are still ongoing. Gadlors are mainly expressed in non-cardiomyocyte derived EVs, and upregulated in human heart failure. In a pre-clinical model of pressure overload, deletion of Gadlor lncRNAs protects from cardiac fibrosis and preserves cardiac function.