J Cardiovasc Pharmacol. 2026 May 15. doi: 10.1097/FJC.0000000000001836. Online ahead of print.
ABSTRACT
Type 2 diabetes mellitus (T2DM) is a critical risk factor for coronary artery disease (CAD), with neutrophils contributing to CAD via acute inflammatory responses. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors offer cardiovascular benefits beyond glycemic control, but their mechanisms involving innate immunity and neutrophil function in T2DM-related CAD remain unclear. Neutrophils were isolated from healthy controls, patients with CAD and T2DM, and patients receiving SGLT2 inhibitor therapy. Bulk transcriptomic analysis, flow cytometry, ELISA, and western blotting were used to assess gene expression, signaling changes, and neutrophil activation.Co-cultures of neutrophils with luciferase-expressing human aortic endothelial cells (HAEC-Luc) assessed endothelial injury, and a diabetic rat model was used to assess in vivo cardiac injury.Results showed elevated peripheral neutrophil counts, cell-free dsDNA, elastase 2, and GREM1 expression in T2DM-CAD patients, reversed by SGLT-2 inhibitors. T2DM-CAD neutrophils induced significant endothelial injury, ameliorated by SGLT-2 inhibition or GREM1 blockade. Mechanistically, SGLT-2 inhibitors suppressed GREM1, restored TGF-β/Smad signaling, and reduced neutrophil-mediated cytotoxicity. In vivo, SGLT-2 inhibitors alleviated cardiac damage in diabetic rat, with suppressed neutrophil activation and upregulated TGF-β signaling. Our findings suggest that increased GREM1 expression in neutrophils is associated with impaired Smad1/5/9-related signaling and enhanced endothelial injury in T2DM-CAD, and SGLT-2 inhibitors exert vascular protection via GREM1 downregulation and TGF-β/Smad pathway modulation, highlighting a novel immunoregulatory mechanism with translational potential for diabetic cardiovascular outcomes.
PMID:42359611 | DOI:10.1097/FJC.0000000000001836