Diminished Α7 Nicotinic Acetylcholine Receptor (α7nachr) Rescues Amyloid-Β Induced Atrial Remodeling by Oxi-Camkii/mapk/ap-1 Axis-Mediated Mitochondrial Oxidative Stress.

The potential coexistence of Alzheimer's disease (AD) and atrial fibrillation (AF) is increasingly common as aging-related diseases. However, little is known about mechanisms responsible for atrial remodeling in AD pathogenesis. alpha 7 nicotinic acetylcholine receptors (alpha 7nAChR) has been shown to have profound effects on mitochondrial oxidative stress in both organ diseases. Here, we investigate the role of alpha 7nAChR in mediating the effects of amyloid-beta (A beta) in cultured mouse atrial cardiomyocytes (HL-1 cells) and AD model mice (APP/PS1). In vitro, apoptosis, oxidative stress and mitochondrial dysfunction induced by A beta long-term (72h) in HL-1 cells were prevented by alpha-Bungarotoxin(alpha-BTX), an antagonist of alpha 7nAChR. This cardioprotective effect was due to reinstating Ca2+ mishandling by decreasing the activation of CaMKII and MAPK signaling pathway, especially the oxidation of CaMKII (oxi-CaMKII). In vivo studies demonstrated that targeting knockdown of alpha 7nAChR in cardiomyocytes could ameliorate AF progression in late-stage (12 months) APP/PS1 mice. Moreover, alpha 7nAChR deficiency in cardiomyocytes attenuated APP/PS1-mutant induced atrial remodeling characterized by reducing fibrosis, atrial dilation, conduction dysfunction, and inflammatory mediator activities via suppressing oxiCaMKII/MAPK/AP-1. Taken together, our findings suggest that diminished alpha 7nAChR could rescue A beta-induced atrial remodeling through oxi-CaMKII/MAPK/AP-1-mediated mitochondrial oxidative stress in atrial cells and AD mice.