S100A11/ANXA2 axis mediates electrotransduction to promote electrically-induced contraction in engineered myocardial tissues

Ischemic heart disease (IHD) manifests impaired myocardial systolic/diastolic and electrophysiological functions due to disrupted electrical integrity. Engineering functional myocardial tissues by modulating extracellular electrical microenvironment represents a promising strategy for cardiac repair; however, the underlying mechanisms driving the maturation of these engineered tissues remain unclear. Using an electrical engineering platform with anisotropic reduced graphene oxide/silk fibroin (rGO/Silk) scaffolds and electrical stimulation (ES), we identified S100 Calcium Binding Protein A11 (S100A11) as a key electroresponsive mediator. S100A11, in complex with Annexin A2 (ANXA2), transduces electrical inputs into augmented calcium dynamics and cytoskeletal remodeling. Specifically, both S100A11 and ANXA2 were upregulated by electrical stimuli, and their complex facilitated the electrophysiological function of neonatal rat cardiomyocytes (NRCMs) by increasing calcium influx, modulating the amplitude/frequency of instantaneous membrane potential (IMP), and boosting calcium-induced calcium release (CICR). Notably, electrical cues triggered nuclear translocation of S100A11 through its interaction with cytoplasmic ANXA2, influenced by β-Tubulin. Nuclear S100A11 upregulated the transcription factors Gata4 and Zfpm1, consequently elevating cytoskeletal components F-actin, α-actinin, and β-Tubulin, which supported sarcomere organization and excitation-contraction (E-C) coupling. These findings highlight the S100A11/ANXA2 axis as a critical electrical-to-biological mediator linking electrical modulation to myocardial tissue maturation, and offering therapeutic implications for cardiac regeneration.