Dataset Information

Upregulated lncRNA Pvt1 may be important for cardiac remodeling at the infarct border zone.

ABSTRACT: Myocardial infarction (MI) is a leading cause of mortality due to progression to ventricular arrhythmias (VAs) or heart failure (HF). Cardiac remodeling at the infarct border zone (IBZ) is the primary contributor for VAs or HF. Therefore, genes involved in IBZ remodeling may be potential targets for the treatment of MI, but the mechanism remains unclear. The present study aimed to explain the molecular mechanisms of IBZ remodeling based on the roles of long non?coding RNAs (lncRNAs). After downloading miRNA (GSE76592) and mRNA/lncRNA (GSE52313) datasets from the Gene Expression Omnibus database, 23 differentially expressed miRNAs (DEMs), 2,563 genes (DEGs) and 168 lncRNAs (DELs) were identified between IBZ samples of MI mice and sham controls. A total of 483 DEGs were predicted to be regulated by 23 DEMs, among which Itgam, Met and TNF belonged to hub genes after five topological parameters were calculated for genes in the protein?protein interaction network. These hub genes?associated DEMs (mmu?miR?181a, mmu?miR?762) can also interact with six DELs (Gm15832, Gas5, Gm6634, Pvt1, Gm14636 and A330023F24Rik) to constitute the competing endogenous RNA (ceRNA) axes. Furthermore, a co?expression network was constructed based on the co?expression pairs between 44 DELs and 297 DEGs, in which Pvt1 and Bst1 were overlapped with the ceRNA network. Thus, Bst1?associated ceRNA (Pvt1?mmu?miR?181a?Bst1) and co?expression (Pvt?Bst1) axes were also pivotal for MI. Accordingly, Pvt1 may be a crucial lncRNA for modification of cardiac remodeling in the IBZ after MI and may function by acting as a ceRNA for miR?181a to regulate TNF/Met/Itgam/Bst1 or by co?expressing with Bst1.

SUBMITTER: Liu B

PROVIDER: S-EPMC7453657 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Upregulated lncRNA Pvt1 may be important for cardiac remodeling at the infarct border zone.

Liu Baihui B Cheng Yuanjuan Y Tian Jiakun J Zhang Li L Cui Xiaoqian X

Molecular medicine reports 20200728 4

Myocardial infarction (MI) is a leading cause of mortality due to progression to ventricular arrhythmias (VAs) or heart failure (HF). Cardiac remodeling at the infarct border zone (IBZ) is the primary contributor for VAs or HF. Therefore, genes involved in IBZ remodeling may be potential targets for the treatment of MI, but the mechanism remains unclear. The present study aimed to explain the molecular mechanisms of IBZ remodeling based on the roles of long non‑coding RNAs (lncRNAs). After downl ...[more]

PMID: 32945428

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Project description:Introduction: Computational models of the heart increasingly require detailed microstructural information to capture the impact of tissue remodeling on cardiac electromechanics in, for example, hearts with myocardial infarctions. Myocardial infarctions are surrounded by the infarct border zone (BZ), which is a site of electromechanical property transition. Magnetic resonance imaging (MRI) is an emerging method for characterizing microstructural remodeling and focal myocardial infarcts and the BZ can be identified with late gadolinium enhanced (LGE) MRI. Microstructural remodeling within the BZ, however, remains poorly characterized by MRI due, in part, to the fact that LGE and DT-MRI are not always available for the same heart. Diffusion tensor MRI (DT-MRI) can evaluate microstructural remodeling by quantifying the DT apparent diffusion coefficient (ADC, increased with decreased cellularity), fractional anisotropy (FA, decreased with increased fibrosis), and tissue mode (decreased with increased fiber disarray). The purpose of this work was to use LGE MRI in post-infarct porcine hearts (N = 7) to segment remote, BZ, and infarcted myocardium, thereby providing a basis to quantify microstructural remodeling in the BZ and infarcted regions using co-registered DT-MRI. Methods: Chronic porcine infarcts were created by balloon occlusion of the LCx. 6-8 weeks post-infarction, MRI contrast was administered, and the heart was potassium arrested, excised, and imaged with LGE MRI (0.33 × 0.33 × 0.33 mm) and co-registered DT-MRI (1 × 1 × 3 mm). Myocardium was segmented as remote, BZ, or infarct by LGE signal intensity thresholds. DT invariants were used to evaluate microstructural remodeling by quantifying ADC, FA, and tissue mode. Results: The BZ significantly remodeled compared to both infarct and remote myocardium. BZ demonstrated a significant decrease in cellularity (increased ADC), significant decrease in tissue organization (decreased FA), and a significant increase in fiber disarray (decreased tissue mode) relative to remote myocardium (all p < 0.05). Microstructural remodeling in the infarct was similar, but significantly larger in magnitude (all p < 0.05). Conclusion: DT-MRI can identify regions of significant microstructural remodeling in the BZ that are distinct from both remote and infarcted myocardium.

Project description:Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined "omics" analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined "omics". Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined "omics" identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone's capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

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Upregulated lncRNA Pvt1 may be important for cardiac remodeling at the infarct border zone.

Publications

Upregulated lncRNA Pvt1 may be important for cardiac remodeling at the infarct border zone.

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