Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis

Abstract

Long non-coding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiovascular diseases, but detailed information about the intercellular lncRNA shuttling mechanisms in the heart is lacking. Here, we report an important novel crosstalk between cardiomyocytes and fibroblasts mediated by the transfer of lncRNA-enriched extracellular vesicles (EVs) in the context of cardiac ischemia. lncRNA profiling identified two hypoxia-sensitive lncRNAs: ENSMUST00000122745 was predominantly found in small EVs, whereas lncRNA Neat1 was enriched in large EVs in vitro and in vivo. Vesicles were taken up by fibroblasts, triggering expression of profibrotic genes. In addition, lncRNA Neat1 was transcriptionally regulated by P53 under basal conditions and by HIF2A during hypoxia. The function of Neat1 was further elucidated in vitro and in vivo. Silencing of Neat1 in vitro revealed that Neat1 was indispensable for fibroblast and cardiomyocyte survival and affected fibroblast functions (reduced migration capacity, stalled cell cycle, and decreased expression of fibrotic genes). Of translational importance, genetic loss of Neat1 in vivo resulted in an impaired heart function after myocardial infarction highlighting its translational relevance.

Exosomes: Beyond stem cells for cardiac protection and repair

“…Hypoxic cardiomyocyte-derived EVs were taken up by fibroblasts and induced expression of profibrotic genes by these cells. 74 homolog/Akt pathway, whereas CPC-derived exosomes from healthy donors attenuated cardiac dysfunction. 77 Also, exosomes from nondiabetic rats protected primary rat cardiomyocytes from hypoxia/ reoxygenation injury via activation of the ERK1/2 and HSP27 pathway, 44 whereas exosomes from Goto Kakizaki type II diabetic rats lacked this ability.…”

Circulating Extracellular Vesicles As Biomarkers and Drug Delivery Vehicles in Cardiovascular Diseases

“…Kenneweg et al [ 101 ] showed lncRNA-enriched EVs in cardiac ischemia. In this context, lncRNA Neat1 was necessary for fibroblast and cardiomyocyte survival, and the silencing of Neat1 resulted in reduced heart function after myocardial infarction.…”

LncRNANEAT1: Shedding light on mechanisms and opportunities in liver diseases

“…120 Moreover, NEAT1 was enriched in large extracellular vesicles secreted by hypoxic cardiomyocytes, which were taken up by fibroblasts, causing the expression of profibrotic genes. 121 However, it has not been reported whether NEAT1 exists in exosomes secreted by liver cells and whether exosome NEAT1 has a certain effect on mediating cellular communications in liver diseases, regardless of origin from the liver or other distant organs. Given that circulating NEAT1 may become a potential biomarker in several liver diseases, it is necessary for future investigators to detect NEAT1 expression in plasma exosomes.…”

“…Notably, NEAT1 was also identified as an exosomal lncRNA, inhibition of which could influence inflammatory responses in inflammatory bowel disease (IBD) through exosome‐mediated polarization of macrophages 120 . Moreover, NEAT1 was enriched in large extracellular vesicles secreted by hypoxic cardiomyocytes, which were taken up by fibroblasts, causing the expression of profibrotic genes 121 . However, it has not been reported whether NEAT1 exists in exosomes secreted by liver cells and whether exosome NEAT1 has a certain effect on mediating cellular communications in liver diseases, regardless of origin from the liver or other distant organs.…”