Chrysophanol Attenuates Cardiac Fibrosis and Arrhythmia by Suppressing the Endoplasmic Reticulum Stress/Pyroptosis Axis and Inflammation

Chrysophanol (CHR), one of the principal bioactive compounds extracted from the rhizome of Rheum palmatum L., is known for its anti-inflammatory, antioxidative, anti-cancer, and cardioprotective effects. However, the effect of CHR on cardiac fibrosis remains elusive. In this study, mice were administered isoproterenol (ISO) to induce cardiac fibrosis in vivo, and cardiac fibroblasts were pretreated with transforming growth factor-β1 (TGF-β1) to induce the transformation of fibroblasts into myofibroblasts in vitro. Western blot and reverse transcription-quantitative polymerase chain reaction analyses were performed to evaluate the endoplasmic reticulum (ER) stress and pyroptosis. Immunohistochemistry staining and ELISA analyses were used to detect the inflammation level. In vivo electrophysiological studies were conducted to assess arrhythmia susceptibility. Our findings revealed that CHR treatment ameliorated cardiac dysfunction and fibrosis in ISO-challenged mice. Moreover, CHR reduced susceptibility to ventricular fibrillation by reducing ventricular electrical remodeling and increasing the expression of gap junction proteins and ion channels. Additionally, CHR inhibited the TGF-β1-stimulated transformation of cardiac fibroblasts into myofibroblasts in vitro. CHR inhibited ER stress, pyroptosis, and inflammation in vivo and in vitro. Furthermore, tunicamycin (TM)-induced activation of ER stress abolished the protective effects of CHR. CHR treatment attenuates cardiac fibrosis and arrhythmia by suppressing the ER stress/pyroptosis axis and inflammation.