IKKε-deficient macrophages impede cardiac repair after myocardial infarction by enhancing the macrophage–myofibroblast transition

The regulatory role of the inhibitor of NF-kB kinase ε (IKKε) in postmyocardial infarction (MI) inflammation remains uncertain. Using an MI mouse model, we examined the cardiac outcomes of IKKε knockout (KO) mice and wild-type mice. We employed single-cell RNA sequencing (scRNA-seq) and phosphorylated protein array techniques to profile cardiac macrophages. IKKε KO mice exhibited compromised survival, heightened inflammation, pronounced cardiac fibrosis, and a reduced ejection fraction. A distinct cardiac macrophage subset in IKKε KO mice exhibited increased fibrotic marker expression and decreased phosphorylated p38 (p-p38) levels, indicating an enhanced macrophage–myofibroblast transition (MMT) post-MI. While cardiac inflammation is crucial for initiating compensatory pathways, the timely resolution of inflammation was impaired in the IKKε KO group, while the MMT in macrophages accelerated post-MI, leading to cardiac failure. Additionally, our study highlighted the potential of 5-azacytidine (5-Aza), known for its anti-inflammatory and cardioprotective effects, in restoring p-p38 levels in stimulated macrophages. The administration of 5-Aza significantly reduced the MMT in cardiac macrophages from the IKKε KO group. These findings underscore the regulation of the inflammatory response and macrophage transition by the IKKε-p38 axis, indicating that the MMT is a promising therapeutic target for ischemic heart disease. Heart attacks can result in heart failure due to ongoing inflammation and scarring. This research investigates how a specific protein, IKKε, affects inflammation in heart cells. Researchers used genetically altered mice and sophisticated genetic methods to study IKKε‘s role in heart disease. They analyzed heart tissue after inducing heart attacks in the mice, focusing on how cells involved in inflammation and scarring behave differently when the IKKε protein is changed. Macrophage-myofibroblast transition (MMT) is a process in which macrophages acquire characteristics similar to myofibroblasts, potentially contributing to tissue fibrosis. The main discovery is that blocking IKKε causes more scarring by encouraging excessive MMT, suggesting it could be a target for heart disease treatment. The researchers believe that controlling the MMT process could be a new method to enhance heart health after a heart attack by reducing harmful scarring. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.