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. 2020 Apr 30;43(4):408-418.
doi: 10.14348/molcells.2020.2164.

Molecular Signatures of Sinus Node Dysfunction Induce Structural Remodeling in the Right Atrial Tissue

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Free PMC article

Molecular Signatures of Sinus Node Dysfunction Induce Structural Remodeling in the Right Atrial Tissue

Seung-Young Roh et al. Mol Cells. .
Free PMC article

Abstract

The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (SND)-characterized by electrical remodeling-is generally attributed to idiopathic fibrosis or ischemic injuries in the SN. SND is associated with increased risk of cardiovascular disorders, including syncope, heart failure, and atrial arrhythmias, particularly atrial fibrillation. One of the histological SND hallmarks is degenerative atrial remodeling that is associated with conduction abnormalities and increased right atrial refractoriness. Although SND is frequently accompanied by increased fibrosis in the right atrium (RA), its molecular basis still remains elusive. Therefore, we investigated whether SND can induce significant molecular changes that account for the structural remodeling of RA. Towards this, we employed a rabbit model of experimental SND, and then compared the genome-wide RNA expression profiles in RA between SND-induced rabbits and sham-operated controls to identify the differentially expressed transcripts. The accompanying gene enrichment analysis revealed extensive pro-fibrotic changes within 7 days after the SN ablation, including activation of transforming growth factor-β (TGF-β) signaling and alterations in the levels of extracellular matrix components and their regulators. Importantly, our findings suggest that periostin, a matricellular factor that regulates the development of cardiac tissue, might play a key role in mediating TGF-β-signaling-induced aberrant atrial remodeling. In conclusion, the present study provides valuable information regarding the molecular signatures underlying SND-induced atrial remodeling, and indicates that periostin can be potentially used in the diagnosis of fibroproliferative cardiac dysfunctions.

Keywords: cardiac fibrosis; periostin; right atrium; sinus node dysfunction; transcriptome; transforming growth factor-β.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Cardiac dysfunctions induced by sinus node damage.
(A) Average heart rate (HR) before the experimental sinus node damage (SNX; upper panel), and the duration (%) for which bradycardia is exhibited 7 days after SND induction (lower panel) in comparison with that in sham-operated controls (CTL). Sinus bradycardia was considered developed at HR < 130 bpm. Data are expressed as mean ± SEM (n = 3 for CTL and 5 for SNX groups; **P < 0.01 by t-test). (B) Increased fibrosis in the RA tissues by SNX. The RA sections were stained with H&E (upper panel) or MTS (lower panel). Scale bars = 50 µm.
Fig. 2
Fig. 2. Genome-wide RNA expression profiles in RA tissues.
(A) Venn diagram (upper panel) and heat map representation with hierarchical clustering (lower panel) of the differentially expressed genes (DEGs) examined 7 days after SNX. RNA levels of 143 genes were significantly higher in the sham-operated controls (CTLs), and 498 RNA levels were higher in the rabbits with SNX. (B) Heat map representation of the top 30 DEGs.
Fig. 3
Fig. 3. Validation of the differential expression of selected mRNA species.
qRT-PCR analyses of the selected DEGs categorized as secretory factors (a), membrane receptors and associated proteins (b), factors involved in extracellular matrix organization (c), actin cytoskeletal subunits (d), and other regulatory factors (e). Relative expression of each mRNA species was normalized to that of the average GAPDH, PPIA, and TBP expression and presented as mean ± SEM in arbitrary units (A.U.), for which the mean expression in the control (CTL) was defined as 1 (n = 3 for CTL [C] and 5 for SND [S] groups; *P < 0.05 and **P < 0.01 by unpaired t-test).
Fig. 4
Fig. 4. Periostin and TGF-β 1 expression at protein levels in cardiac tissues.
(A)Representativeimagesdepictingthe expressionofperiostin,TGF-β1,andβ-actinproteinsinvarious myocardial tissues as evaluated by immunoblot (RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle). (B) Expression ofperiostinandTGF-β1proteinsnormalizedtothatofβ-actin ispresentedasmean±SEMinarbitraryunits(A.U.),forwhich the mean expression in the control (CTL) was defined as 1 (n = 3 for CTL and 5 for the SNX groups; *P < 0.05 and **P < 0.01 by unpaired t-test).

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