Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction in murine models

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE322635 | GEO | 2026/06/03

REPOSITORIES: GEO