Long non-coding RNA MALAT1 promotes cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD.

Dan Li,Yuxin Xian,Caixia Cao,Xuecheng Yang,Jinna Che,Chunling Zhang,Jian Li,Xueli Li

doi:10.18632/aging.102265

Abstract

Hypertension is the leading preventable cause of premature deaths worldwide. Although long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been identified to play important roles in the development of cardiovascular diseases, the regulatory function of lncRNA MALAT1 in hypertension remains poorly understood. This study aimed to explore the role of lncRNA MALAT1 in spontaneously hypertensive rats (SHRs). LncRNA MALAT1 was determined to be elevated and MyoD to be reduced in myocardial tissues and thoracic aortic vascular tissues of SHRs. Over-expression of lncRNA MALAT1 caused severe myocardial fibrosis in SHRs. In addition, lncRNA MALAT1 over-expression in vitro enhanced arterial smooth muscle cells (ASMCs) activity and fibrosis of SHRs, which, was rescued by over-expressed MyoD. Furthermore, lncRNA MALAT1 transcripts were found to be highly enriched in the nucleus, and lncRNA MALAT1 suppressed the transactivation of MyoD. Moreover, lncRNA MALAT1 was found to recruit Suv39h1 to MyoD-binding loci, leading to H3K9me3 trimethylation and down-regulation of the target gene. Taken conjointly, this study revealed an important role of lncRNA MALAT1 in promoting cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD. These results highlight the value of lncRNA MALAT1 as a therapeutic target for the management of hypertension.

Highlights

Hypertension is a universal health challenge owing to its high prevalence and resultant cardiovascular disease and chronic kidney disease [1]
The results revealed that the left ventricle weight (LVW) and LVW/body weight (BW) in spontaneously hypertensive rats (SHRs) were significantly higher than those in SD rats and the SHRs presented with mild myocardial fibrosis, severe perivascular fibrosis, hypertrophic myocardial cells, and increased cross-section area of myocardial cells (Figure 1B–1D)
reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were conducted to determine the expression of long non-coding RNA (lncRNA) Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and MyoD in arterial smooth muscle cells (ASMCs) of SHRs and the results showed that compared with the lentiviral vector (LV)-CON-vector group, the expression of lncRNA MALAT1 did not differ while that of MyoD was increased in ASMCs in the LV-MyoD-vector group, which was in line with the trend observed in the LV-MALAT1 + LV-MyoDvector group when compared to the LV-MALAT1 + LV-CON-vector group (Figure 6A–6C)

Summary

Introduction

Hypertension is a universal health challenge owing to its high prevalence and resultant cardiovascular disease and chronic kidney disease [1]. Hypertension, as the leading preventable risk factor for disability and premature deaths worldwide, may be attributed to genetic, epigenetic and environmental factors [2, 3]. The processes of pulmonary vascular remodeling and obliteration of the vessel lumen are implicated in hypertension, which is believed to result in right ventricular failure and premature death [5]. Long non-coding RNAs (lncRNAs) are transcribed genomic regions (longer than 200 nucleotides) without the ability to code for proteins [6]. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that is highly conserved among mammals, and known as noncoding nuclear-enriched abundant transcript 2 [7]. MALAT1 promotes cell proliferation by regulating the transcription and/or post-transcription modification of cell cycle-mediated transcription factors [8].

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