Humanin and MOTS-c attenuate atrial fibrillation by suppressing fibrosis and mitochondrial dysfunction
Background
Atrial fibrillation (AF) is the most prevalent clinical arrhythmia, leading to severe consequences like stroke and heart failure. Current therapies, including rate and rhythm control, often fail to improve patient outcomes. A core pathophysiological mechanism is atrial electrical and structural remodeling, with atrial fibrosis being a central component. Mitochondrial dysfunction and oxidative stress are also implicated. Mitochondrial-derived peptides (MDPs) like Humanin and MOTS-c possess cytoprotective properties, offering a novel therapeutic avenue for AF by targeting these underlying mechanisms.
Study Design
Researchers investigated the role of Humanin (HN) and MOTS-c in atrial fibrillation (AF). They first analyzed human AF atrial tissue and plasma from AF patients to assess endogenous peptide levels and their correlation with disease markers. Subsequently, they conducted in vivo experiments where animal models of AF received either HNG or MOTS-c treatment. The primary endpoints included AF inducibility, assessment of atrial remodeling, fibrosis markers, and mitochondrial function using various biochemical and histological assays.
Results
In human AF atrial tissue, Humanin and MOTS-c levels were found to be significantly downregulated, with an inverse correlation observed between their levels and the extent of fibrosis. Plasma MOTS-c was also decreased in AF patients and inversely correlated with NT-proBNP, a biomarker for heart failure. This suggests a potential diagnostic or prognostic role for these peptides. In vivo, treatment with HNG or MOTS-c effectively reduced AF inducibility and attenuated atrial remodeling. Both peptides suppressed atrial fibrosis and improved mitochondrial function, indicating a direct protective role against AF pathophysiology.
Specifically, HNG or MOTS-c treatment attenuated atrial remodeling, suppressed atrial fibrosis, and improved mitochondrial function in AF models.
Key Findings
- Humanin and MOTS-c levels were significantly downregulated in human AF atrial tissue.
- Plasma MOTS-c was decreased in AF patients and inversely correlated with
NT-proBNP. HNGorMOTS-ctreatment reduced AF inducibility in vivo.HNGorMOTS-cattenuated atrial remodeling and suppressed fibrosis.HNGorMOTS-cimproved mitochondrial function in AF models.
Why It Matters
This research highlights Humanin and MOTS-c as promising therapeutic candidates for atrial fibrillation (AF), offering a novel approach beyond current rate and rhythm control strategies. By targeting fundamental mechanisms like fibrosis and mitochondrial dysfunction, these peptides could address the structural remodeling driving AF perpetuation. The findings suggest a potential for developing new drugs that improve mitochondrial health and reduce atrial scarring, potentially leading to more effective AF prevention or treatment. While preclinical, this work lays the groundwork for future clinical trials, suggesting that optimizing mitochondrial function could be a key strategy in AF management.
humanin
mots-c
atrial-fibrillation
fibrosis
mitochondrial-dysfunction
preclinical-animal