CACNB2 overexpression suppresses atrial fibroblast activation and atrial fibrosis to mitigate atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity and mortality due to complications such as stroke and heart failure. Cardiac fibrosis creates a pathological substrate for AF and remains inadequately addressed by current therapies. The Calcium Channel subunit CACNB2 has emerged as an underlying regulator of cardiac electrophysiology and fibrosis, yet its effects in the context of AF and atrial fibrosis remain poorly understood. In this study, CACNB2 was identify as a novel anti-fibrotic target in AF, demonstrating that CACNB2 overexpression in a rat AF model significantly improved electrophysiological parameters, including normalization of atrial effective refractory period (AERP), reappearance of regular P waves, and shortened AF duration, and mitigated atrial fibrosis and inflammation by reducing α-SMA, Collagen I, and Collagen III expression and inflammatory cytokine levels. In vitro, CACNB2 overexpression attenuated the profibrotic effects of Ang II on primary atrial fibroblasts, including reductions in cell viability and fibrotic marker expression. Also, CACNB2 overexpression modulated calcium handling and cellular oxidative stress responses in primary atrial cardiomyocytes under Ang II stimulation. This protective effect was accompanied by a modulation of the TGF-β/Smad pathway, suggesting a direct regulatory effect of CACNB2 on this fibrotic process. Collectively, our findings reveal that CACNB2 overexpression plays a protective role against AF and cardiac fibrosis by improving electrophysiological stability, reducing fibrotic remodeling, and modulating fibroblast and cardiomyocytes phenotype and function. These results highlight the novel therapeutic potential of targeting CACNB2 to treat AF and prevent its progression by addressing the underlying atrial fibrosis, offering a promising avenue for future research and development of novel AF therapies.

Atrial fibrillation (AF); Atrial fibroblast; Atrial fibrosis; CACNB2; The TGF-β/Smad signaling pathway.