Biochem Pharmacol. 2026 Mar 24. pii: S0006-2952(26)00261-3. [Epub ahead of print]
117928
Myocardial ischemia/reperfusion (I/R) is the preferred treatment for acute myocardial infarction, yet it still results in cardiomyocytes (CMs) injury. Sodium ion is essential for maintaining ionic balance and bioelectrical activity in CMs. However, whether sodium ion overload leads to CMs Necrosis by Sodium Overload (NECSO) remains uncertain. In this study, CoroNa Green revealed that I/R induces sodium ion accumulation in CMs, triggering NECSO. Under I/R conditions, culturing CMs in Low Na+ medium resulted in a significant decrease in the number of NECSO-positive cells. Subsequent intervention with the Trpm4-targeted activator Desacetyl bisacodyl (DAB) and inhibitor Clotrimazole (CLT) demonstrated that either activation or inhibition of Trpm4 could profoundly modify the extent of I/R-induced CMs injury. By employing multiple machine learning algorithms, we pinpointed St3gal5 and Tspan4 as core NECSO-related genes (NRGs), with Tspan4 exerting its effects mainly through Tspan4-positive fibroblasts (FBs). Research indicated that co-culturing Tspan4+ FBs with CMs under I/R conditions significantly increases NECSO incidence. This effect arises not from migrasomes directly acting on CMs, but from migrasomes regulating FBs to upregulate tumor necrosis factor-α (Tnf-α), which in turn elevates the protein level of Cyp11b2 (the key rate-limiting enzyme for aldosterone synthesis), thereby ultimately inducing NECSO in CMs. In vivo experiments demonstrated that eplerenone significantly improves prognosis, suggesting its potential as a research drug for preventing and treating NECSO in CMs.
Keywords: Aldosterone; Fibroblasts; Migrasomes; Myocardial ischemia reperfusion; NECSO