Abstract
Dilated cardiomyopathy (DCM) is a relatively common cause of heart failure and the leading cause of heart transplantation. Aberrant changes in long non-coding RNAs (lncRNAs) are involved in DCM disorder; however, the detailed mechanisms underlying DCM initiation and progression require further investigation, and new molecular targets are needed. Here, we obtained lncRNA-expression profiles associated with DCM and non-failing hearts through microarray probe-sequence re-annotation. Weighted gene co-expression network analysis revealed a module highly associated with DCM status. Then eight hub lncRNAs in this module (FGD5-AS1, AC009113.1, WDFY3-AS2, NIFK-AS1, ZNF571-AS1, MIR100HG, AC079089.1, and EIF3J-AS1) were identified. All hub lncRNAs except ZNF571-AS1 were predicted as localizing to the cytoplasm. As a possible mechanism of DCM pathogenesis, we predicted that these hub lncRNAs might exert functions by acting as competing endogenous RNAs (ceRNAs). Furthermore, we found that the above results can be essentially reproduced in an independent external dataset. We observed the localization of hub lncRNAs by RNA-FISH in human aortic smooth muscle cells and confirmed the upregulation of the hub lncRNAs in DCM patients through quantitative RT-PCR. In conclusion, these findings identified eight candidate lncRNAs associated with DCM disease and revealed their potential involvement in DCM partly through ceRNA crosstalk. Our results facilitate the discovery of therapeutic targets and enhance the understanding of DCM pathogenesis.
Highlights
Dilated cardiomyopathy (DCM) is a myocardial disorder defined by the presence of left ventricular or biventricular dilatation and left ventricular systolic impairment that are not explained by coronary artery disease or abnormal loading conditions (Elliott et al, 2008)
We identified 104 differentially expressed Long non-coding RNAs (lncRNAs) (DElncRNAs) and 1,867 differentially expressed mRNAs (DEmRNAs) between DCM patients and control subjects in GSE21610
Pathway enrichment analysis showed upregulated DEmRNAs were associated with 5-hydroxytryptamine degradation, circadian clock system, adrenaline and noradrenaline biosynthesis, pyrimidine metabolism, and gamma-aminobutyric acid synthesis, which were closely related to pathophysiology of DCM and heart failure (Figure 2D)
Summary
Dilated cardiomyopathy (DCM) is a myocardial disorder defined by the presence of left ventricular or biventricular dilatation and left ventricular systolic impairment that are not explained by coronary artery disease or abnormal loading conditions (Elliott et al, 2008). Further investigation of the mechanisms underlying DCM initiation and progression is required, and new molecular targets are urgently needed. Emerging evidence reveals critical roles for lncRNAs in the development and progression of cardiovascular diseases (Lovren et al, 2012; Han et al, 2014; Micheletti et al, 2017; Zhang et al, 2018), and several studies report dysregulation of lncRNAs in association with DCM (Frade et al, 2016; Li et al, 2018a; Huang et al, 2019; van Heesch et al, 2019; Zhang et al, 2019; Zhou et al, 2019). The mechanisms associated with lncRNA-specific regulation of DCM initiation and progression remain vague
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