Lenalidomide attenuates cardiac fibrosis and inflammation induced by β-adrenergic receptor activation.

β-Adrenergic receptor (β-AR) excessive activation assumes a vital role in various cardiovascular diseases and mediates cardiac fibrosis and cardiac inflammation. Lenalidomide (Len) has shown anti-fibrosis effects in diverse fibrotic diseases. However, it is unclear whether and how Len suppresses cardiac fibrosis and cardiac inflammation triggered by β-AR overactivation. In our research, mice were treated in the presence of or in the absence of the β-AR agonist isoproterenol (ISO) and with or without Len pretreatment. Interestingly, the results showed that Len alleviated β-AR-induced cardiac dysfunction and cardiac fibrosis by PI3K/AKT and ERK signalings in vivo. Consistently, Len also attenuated β-AR-induced cardiac fibroblasts activation by PI3K/AKT and ERK signalings in vitro. Besides, Len suppressed β-AR-induced cardiac inflammation by PI3K/AKT and NF-κB signalings in vivo. Similarly, Len inhibited β-AR-induced macrophages pro-inflammatory cytokines expression by PI3K/AKT and NF-κB signalings in vitro. To further explore the protective mechanism of Len, we used KEGG enrich analysis and found that Len functioned in therapeutic effects by targeting AKT1 in both cardiac fibroblasts and macrophages. In summary, our study demonstrated that Len ameliorated cardiac fibrosis and cardiac inflammation upon β-adrenergic insult. And the mechanism suggested that Len function in cardiac fibrosis and inflammation via targeting AKT1.