IL-37 Modulates Myocardial Calcium Handling via the p-STAT3/SERCA2a Axis in HF-Related Engineered Human Heart Tissue.

Abstract

Interleukin-37 (IL-37) is a potent anti-inflammatory cytokine belonging to the IL-1 family. This study investigates the regulatory mechanism and reparative effects of IL-37 on HF-related human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) and engineered human heart tissue subjected to hypoxia and H₂O₂ treatment. The contractile force and Ca²⁺ conduction capacity of the tissue are assessed using a stretching platform and high-resolution fluorescence imaging system. This investigation reveals that IL-37 treatment significantly enhances cell viability, calcium transient levels, contractile force, and Ca²⁺ conduction capacity in HF-related hiPSC-CMs and engineered human heart tissue. Notably, IL-37 facilitates the upregulation of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) through enhancing nuclear p-STAT3 levels. This effect is mediated by the binding of p-STAT3 to the SERCA2a promoter, providing a novel insight on the reparative potential of IL-37 in HF. IL-37 demonstrates its ability to enhance systolic function by modulating myocardial calcium handling via the p-STAT3/SERCA2a axis in HF-related engineered human heart tissue (as shown in schematic diagram).