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Proteomic sequencing of atrial fibrosis rat model caused by chronic intermittent hypoxia

ABSTRACT: This study was aimed to understand the changes of proteins occurring in atrial tissue of atrial fibrillation (AF) rat model based on proteome sequencing.SD rats were used for AF model construction by chronic intermittent hypoxia (CIH) induction. The tissue pathological changes were observed by hematoxylin-eosin staining, masson staining, and immunohistochemistry analysis of the levels of fibrosis biomarkers. Then proteome sequencing was performed on atrial fibrosis samples to identify the differentially expressed proteins (DEPs) between CIH and control groups, following by functional analysis. The protein levels of several key proteins were validated by western blotting.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Xue Liang

PROVIDER: PXD042312 | iProX | Thu May 18 00:00:00 BST 2023

REPOSITORIES: iProX

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Project description:Background. A recent study identified a rare variant in the MRC2 gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) ECG pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and MRC2 was recently proposed as a protective gene for AF. Objective. We aimed to determine whether the E990G-heterozygous (het) loss-of-function variant in MRC2 increases AF susceptibility and aberrant atrial cardiofibroblast (ACF) function in mice. Methods. Programmed electrical stimulation (PES) was performed to determine AF susceptibility in E990G-het mice and wild-type (WT) controls. ACFs were isolated from these mice and cultured, and their migration, and collagen deposition were quantified. Finally, transcriptomic profiling by RNA sequencing and secretomic/proteomic profiling by mass spectrometry were performed on ACFs and whole atrial tissue. Results. E990G-het mice exhibited increased susceptibility to pacing-induced AF and had decreased atrioventricular effective refractory periods compared to WT controls. ACFs isolated from E990G-het mice deposited greater amounts of acid-soluble collagen in 2D cultures as quantified by Sirius red staining compared with WT controls. Transcriptomic, secretomic, and proteomic profiling of cultured ACFs and whole-atrial tissue suggest that some fibrotic regulators are differentially expressed or secreted, including decreased ACF expression of matrix metalloproteinase 13 (MMP-13), which degrades collagen types I, II, and III; decreased ACF expression, ACF secretion, and atrial tissue levels of matrix metalloproteinase 12 (MMP-12), which degrades collagen types I, III, IV, elastin, and fibronectin; and increased tissue levels of cellular communication network factor 2/connective tissue growth factor (CCN2/CTGF), a profibrotic regulator. Conclusions. MRC2 E990G-het mice exhibit increased AF susceptibility, altered collagen deposition by ACFs, and differentially regulated fibrotic genes and proteins. Together, these findings suggest that excessive collagen deposition and reduced MMP-mediated collagen removal generate a substrate for the development of AF in the presence of a loss-of-function variant in MRC2.

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Proteomic sequencing of atrial fibrosis rat model caused by chronic intermittent hypoxia

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