A critical role for IL-21/IL-21 receptor signaling in isoproterenol-induced cardiac remodeling

Increased cytokine secretion from immune cells is often associated with cardiac remodeling and heart failure due to pressure overload. Several reports suggest that the IL-21/IL-21 receptor (IL-21R) signaling pathway may play a critical role in heart failure progression, but the exact mechanism remains unclear. In this study, isoproterenol (ISO) was used to induce heart failure in mice and found that ISO injection caused significant upregulation of IL-21 and the IL-21R in the heart of mice. Subsequently, IL-21 receptor-deficient (IL-21R^-/-) mice were used to evaluate the cardioprotective effects of IL-21/IL-21R. Importantly, we found a significant reduction in myocardial hypertrophy, inflammation, and apoptosis in ISO-treated IL-21R^-/- mice compared to WT mice. Furthermore, the frequency of CD4⁺IFN-γ⁺ cells was significantly reduced in ISO-treated IL-21R^-/- mice. Co-culture studies showed that the adhesion rate of CD4⁺ T cells isolated from IL-21R^-/- to cardiac fibroblasts was significantly reduced compared to co-cultures isolated from WT mice. Accordingly, significant downregulation of α-SMA was detected in cardiac fibroblasts when cocultured with CD4⁺ T cells isolated from IL-21R^-/- mice. Furthermore, IL-21 could directly induce cardiomyocyte hypertrophy and apoptosis and exacerbate ISO-induced myocardial damage through activation of STAT3 signaling pathway. Our study demonstrates the mechanism of IL-21 and its receptor in the progression of myocardial hypertrophy and fibrosis and highlights that the absence of IL-21R may provide protection against myocardial damage, thus providing a new potential therapeutic target for the treatment of heart failure.