Long noncoding RNA NEAT1 promotes cardiac fibrosis in heart failure through increased recruitment of EZH2 to the Smad7 promoter region

Abstract

Cardiac fibrosis, a well-known major pathological process that ultimately leads to heart failure, has attracted increasing attention and focus in recent years. A large amount of research indicates that long noncoding RNAs (lncRNAs) play an important role in cardiac fibrosis, but little is known about the specific function and mechanism of the lncRNA NEAT1 in the progression of cardiac fibrosis to heart failure. In the present study, we have demonstrated that the lncRNA NEAT1 is upregulated in patients with heart failure. Similarly, the expression of Neat1 was also increased in the left ventricular tissue of transverse aortic constriction (TAC) surgery mice and cardiac fibroblasts treated with TGF-β1. Further, gain-of-function and loss-of-function experiments showed that silencing of Neat1 attenuated cardiac fibrosis, while overexpression of Neat1 with adenovirus significantly aggravated the in vitro progression of fibrosis. With regard to the underlying mechanism, our experiments showed that Neat1 recruited EZH2 to the promoter region of Smad7 through physical binding of EZH2 to the promoter region, as a result of which Smad7 expression was inhibited and the progression of cardiac fibrosis was ultimately exacerbated. We found that the introduction of shNeat1 carried by adeno-associated virus-9 significantly ameliorated cardiac fibrosis and dysfunction caused by TAC surgery in mice. Overall, our study findings demonstrate that the lncRNA Neat1 accelerates the progression of cardiac fibrosis and dysfunction by recruiting EZH2 to suppress Smad7 expression. Thus, NEAT1 may serve as a target for the treatment of cardiac fibrosis.

Gene amplification-driven lncRNA SNHG6 promotes tumorigenesis via epigenetically suppressing p27 expression and regulating cell cycle in non–small cell lung cancer

“…EZH2 is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2) and functions as a methyltransferase to mediate H3K27 trimethylation in the promoter region of target genes [ 45 , 46 ]. It reported that several lncRNAs could interact with EZH2 to epigenetically suppress the expression of the downstream gene [ 47 – 49 ]. For instance, CASC9 promoted esophageal squamous cell carcinoma (ESCC) progression by negatively regulating PDCD4 expression through recruiting EZH2 [ 50 ].…”

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

“…NEAT1 has been previously associated with matrix remodeling, but with contradictory results depending on the analysis method used. Several studies associated NEAT1 overexpression with fibrosis progression and also with fibrosis reduction [ 65 , 66 , 67 , 68 ]. Nevertheless, studies of matrix remodeling did not analyze NEAT1 at the isoform level.…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…lncRNA-ANRIL alters the expression of fibronectin (FN), type IV collagen (Col1α4), and VEGF by interacting with multiple epigenetic regulators, including EZH2, p300, and regulates cardiac fibrosis in diabetic mice [ 107 ]. Furthermore, LncRNA NEAT1 inhibits Smad7 expression by recruiting EZH2 to the Smad7 promoter region, which ultimately aggravates the progression of cardiac fibrosis, while silencing NEAT1 significantly ameliorates TAC surgery-induced cardiac fibrosis and dysfunction in mice [ 108 ]. Moreover, in spontaneously hypertensive rats (SHRs), SUV39H1 is recruited by lncRNA MALAT1, resulting in H3K9me3 of MyoD-binding loci to mediate cardiac fibrosis [ 110 ].…”