Interleukin-33 induces angiogenesis after myocardial infarction via AKT/eNOS signaling pathway

• IL-33 improves cardiac function and promotes angiogenesis after myocardial infarction. • Activating eNOS and AKT, and mediating NO production involves in the angiogenic effect of IL-33 under hypoxic condition. • Nanocarry system loaded IL-33 shows potential to protect myocardium from ischemia and alleviate inflammatory in clinic. Myocardial infarction (MI) is one of the leading causes of mortality and morbidity worldwide. MI-damaged vascular structures are difficult to completely restore due to the heart’s low regenerative capacity. Given interleukin-33 (IL-33) as a potent endothelial activator promoting angiogenesis, this study investigated the role of IL-33 in angiogenesis and cardiac repair after MI. A mouse model of MI was established. IL-33 improved cardiac function and induced an increase in vascular density after MI. Besides, IL-33 promoted human endothelial cells proliferation, migration, and differentiation under both normoxic and hypoxic conditions, consistently with increased angiogenesis in vivo. Mechanistic studies demonstrated that IL-33 could promote angiogenesis by activating eNOS and AKT, and stimulating NO production in vivo and in vitro. Given that injection of exogenous IL-33 induced an inflammatory response, we employed a multifunctional biomimetic nanoparticle drug delivery system to deliver IL-33, thereby enhancing its targeting to the heart for fibrotic therapy and reducing inflammation. In conclusion, our results indicate that IL-33 promotes endothelial angiogenesis after MI through AKT/eNOS/NO signaling pathway. PM&EM/IL-33 nanoparticles may hold promising therapeutic potential for protecting cardiac ischemic injury and mitigating inflammation.