抄録
Structural remodeling in atrial fibrillation (AF) is mainly evidenced by interstitial fibrosis. Angiotensin II downstream induces TGF-β mRNA expression. Primarily, TGF-β acts through the Smad signaling pathway to stimulate collagen production. TGF-β can affect atrial myocytes via autocrine and/or paracrine mechanisms. Our experimental results indicate that rapid activation in atrial myocytes promotes myofibril degradation through an autocrine TGF-β signaling and increased oxidative stress. Inhibition of both atrial tachycardia-induced autocrine effect and oxidative stress represents a useful target for therapeutic intervention in AF. Several studies have indicated that AF is often accompanied by oxidative changes, which include up-regulation of NADPH oxidase (Nox), a major producer of ROS. The ROS can be also mediated by the RAAS. ROS activates ERKs, JNK and p38-MAPK in both atrial myocytes and fibroblasts. The pro-fibrotic effects of ROS involve an increase in fibroblast proliferation, the expression of pro-fibrotic genes and alterations in extracellular matrix metabolism. Recently, we have also shown atrial fibroblasts exhibiting greater fibrotic and oxidative responses to TGF-β than ventricular fibroblasts in adult male Wistar rats. Nox4-derived ROS production mediates the susceptibility of atrial fibroblasts to TGF-β via activating TGF-β/Smad signaling cascade, which represents a novel mechanism linking atrial fibrosis to the pathogenesis of AF. In Conclusion, understanding the molecular mechanisms that mediate atrial fibrosis may promote novel approaches for AF management in the future.
