Berberine Stabilizes the Arrhythmogenic Substrate in Obese Rats by Klotho-Mediated Attenuation of Oxidative Stress and Inflammation

Obesity increases susceptibility to ventricular arrhythmias due to an arrhythmogenic substrate by promoting oxidative stress and inflammation-driven cardiac remodeling. Klotho, an anti-aging protein that is reduced in obesity-related cardiovascular disease, protects against oxidative injury and inflammation. Berberine (BBR) has been demonstrated to have antiarrhythmic properties, but Klotho mediates these effects in obesity remains unclear. Here, high-fat diet (HFD)-induced obese rats were treated with BBR for 8 weeks. Surface electrocardiography showed BBR shortened prolonged QT, QTc, and Tp-Te intervals. Optical mapping of isolated hearts revealed that BBR eliminated arrhythmia susceptibility (60% to 0%) and stabilized cardiac electrophysiology by shortening action potential duration (APD50/APD90), reducing repolarization dispersion, normalizing conduction velocity, and improving abnormal intracellular Ca2+ handling. BBR also attenuated cardiac hypertrophy and fibrosis and increased expression of the potassium channel subunits Kv4.2, Kv4.3, and KChIP2. Furthermore, BBR suppressed oxidative stress and inflammation while upregulating circulating and tissue Klotho levels in obese rats. In ox-LDL-treated H9C2 cells, Klotho silencing abolished the antioxidative and anti-inflammatory effects of BBR, indicating that Klotho is required for its cardioprotective actions. These findings demonstrate that BBR stabilizes the arrhythmogenic substrate in obesity-related cardiac remodeling, at least partly through upregulation of Klotho expression and subsequent attenuation of oxidative stress and inflammation.