Overexpression of BMP10 mitigated pacing-induced atrial fibrillation incidence and increased conduction velocity in aged rats by improving mitochondrial function via STAT3 signaling.
Does BMP10 overexpression reduce pacing-induced atrial fibrillation susceptibility in aged rats?
BMP10 overexpression protects against age-related atrial fibrillation by improving mitochondrial function and reducing ROS production via STAT3 signaling in atrial cardiomyocytes.
• Upregulated BMP10 expression is associated with age-related atrial fibrillation. • Overexpressing BMP10 alleviates age-related atrial fibrillation susceptibility via improving mitochondrial function. • BMP10 contributes to a translocation of phosphorylated STAT3 into mitochondria to reduce ROS production in atrial cardiomyocytes. Although emerging clinical studies exhibit a strong association of circulating bone morphogenetic protein (BMP10) level with adverse outcomes in patients with atrial fibrillation (AF), also in older individuals. The exact role of BMP10 in age-related AF pathogenesis and potential mechanisms remain unknown. Aged rats were subjected to injection of negative control (NC) or adeno-associated virus 9 (AAV9) to overexpress BMP10, then intracardiac electrophysiology, echocardiography and histology were performed after 4 weeks. Proteomics was conducted to reveal the differential proteins in rat atria. Mitochondrial morphology, reactive oxygen species (ROS) and metabolic substrates were assessed by transmission electron microscopy, mitoSOX and testing assay. Aged rats and AF patients exhibited elevated serum BMP10 levels compared to young controls. Increased BMP10 protein expression correlated with atrial remodeling and AF phenotype of aged rats compared to young rats. Overexpression of BMP10 mitigated the pacing-induced AF incidence and increased conduction velocity compared to controls. Atrial fibrosis, inflammatory foci were reduced with restored electrical activity in AAV-BMP10 treated rats. Proteomics indicated improved atrial mitochondrial metabolism related to signal transducer and activator of transcription 3 (STAT3) signaling in AAV-BMP10 injection rats. Overexpressing BMP10 diminished ROS production by regulating phosphorylation of STAT3 translocation into mitochondria. Moreover, overexpressing BMP10 stimulated mitochondrial electron transport chain complexes to generate more ATP by upregulating biogenesis makers in atrial cardiomyocytes. Our work demonstrates that BMP10 alleviates age-related atrial arrhythmogenesis via mitochondrial STAT3 impacts in atrial cardiomyocytes. BMP10 activates the phosphorylation of STAT3 signaling pathway by a BMP non-canonical pathway in atrial cardiomyocytes. Phosphorylated STAT3 can translocate into mitochondria, which prevents mitochondrial-specific ROS and increases ATP production in atrial cardiomyocytes. The beneficial effect of BMP10 diminishes the susceptibility of aged-related atrial fibrillation via mitochondrial impacts. (ATP, adenosine triphosphate; BMP, bone morphogenetic protein; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3)
Gao et al. (Tue,) conducted a other in Age-related atrial fibrillation. Adeno-associated virus 9 (AAV9) to overexpress BMP10 vs. Negative control (NC) was evaluated on Pacing-induced AF incidence and conduction velocity. Overexpression of BMP10 mitigated pacing-induced atrial fibrillation incidence and increased conduction velocity in aged rats by improving mitochondrial function via STAT3 signaling.