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Selective blockade of microRNA-31-5p/calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden

ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is promoted by atrial fibrosis, a form of structural remodelling for which effective therapies are lacking. MicroRNA-31-5p (miR-31-5p), an ageing-associated, atrial-enriched microRNA, has been linked to AF, but its role in atrial fibrosis is unknown. Here we show that atrial fibroblasts from patients with persistent AF exhibit increased miR-31-5p expression and reduced expression of the calcitonin receptor (CTR, encoded by CALCR). MiR-31-5p directly represses CTR and promotes profibrotic fibroblast responses, whereas its inhibition restores CTR expression. Fibroblast-specific overexpression of miR-31 in mice reduces atrial CTR expression, increases atrial fibrosis and enhances arrhythmia susceptibility. Selective disruption of miR-31-5p/CALCR binding using a locked nucleic acid target-site blocker restores atrial CTR expression, prevents fibrosis progression and reduces arrhythmia burden. In mice with established atrial remodelling, this strategy promotes fibrosis regression, identifying the miR-31-5p/CTR axis as a potential therapeutic target in AF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294333 | GEO | 2026/09/11

REPOSITORIES: GEO

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Project description:BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia associated with mitochondrial dysfunction, oxidative stress, and atrial fibrosis. Mitochondrial-derived peptides (MDPs) including humanin (HN) and MOTS-c, demonstrated potent cytoprotective effects, but their role in AF remains elusive. METHODS: Public GEO database, immunohistochemistry and immunofluorescence were applied to determine their expressions in atrial tissues. Plasma peptide levels were measured in a clinical cohort. Murine AF models and primary rat cardiomyocytes and fibroblasts models were established by administration of angiotensin II (Ang II) and treated with (Gly14)-Humanin (HNG, an HN analogue) or MOTS-c. RESULTS: Both HN and MOTS-c gene expressions were significantly downregulated in human AF atrial tissue and negatively correlated with the extent of fibrosis. Plasma MOTS-c level decreased in AF patients and showed an inverse correlation with NT-proBNP. In vivo, administration of HNG or MOTS-c significantly reduced AF inducibility, attenuated atrial fibrosis and hypertrophy induced by Ang II. Furthermore, HNG or MOTS-c treatment improved mitochondrial ultrastructure, as well as downregulated the expressions of mitochondrial fission proteins (Drp1 and Fis1) and pro-inflammatory cytokines (IL-1β and IL-6) of atrial tissue in murine AF models. In primary cardiomyocytes, both peptides mitigated Ang II-induced oxidative stress. In addition, they directly inhibited Ang II-induced fibroblast activation, proliferation, and migration in vitro. Further RNA sequencing results suggested that HNG mainly affects cell adhesion pathways and MOTS-c acts on metabolic process of cardiac fibroblasts. CONCLUSIONS: The downregulation of HN and MOTS-c in human AF is associated with AF severity. Administration of HNG or MOTS-c effectively suppressing atrial fibrosis and mitochondrial dysfunction and prevents AF in murine models. Therefore, mitochondrial-derived peptides represent as the underappreciated contributor to AF therapy and potential biomarkers.

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Selective blockade of microRNA-31-5p/calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden

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