Abstract
Diabetes mellitus significantly exacerbates myocardial ischemia-reperfusion (I/R) injury, leading to adverse remodeling and heart failure, yet the precise cellular dynamics governing this process remain incompletely understood. Cardiac macrophages are pivotal mediators of post-ischemic injury and repair, but their intrinsic heterogeneity in the diabetic context has not been fully mapped. In this study, we applied single-cell RNA sequencing (scRNA-seq) to profile CD45+ CD11b+ cardiac macrophages isolated from streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats subjected to 45 minutes of transient left anterior descending coronary artery occlusion followed by 72 hours of reperfusion. Transcriptomic clustering revealed six distinct macrophage subpopulations with unique molecular signatures. Diabetic hearts exhibited a striking expansion of a hyper-inflammatory subpopulation characterized by elevated expression of Spp1, Nlrp3, and Il1b, coupled with a marked suppression of repair-associated macrophage clusters expressing Trem2 and Mrc1. Pseudotime trajectory analysis demonstrated a stalled maturation pathway from inflammatory to pro-resolving states in diabetic cardiac tissue. These findings demonstrate that diabetes disrupts the transcriptomic programming of cardiac macrophages during I/R, persistent driving tissue destruction and blunting reparative transition, thereby offering novel therapeutic targets for immunomodulation in diabetic ischemic heart disease.
