Synergistic SGLT2 and GLP-1R targeting alleviates systemic inflammation-induced and M1 monocyte-driven endothelial dysfunction in coronary artery disease.

BACKGROUND AND

objectiveSystemic residual inflammation plays a pivotal role in the pathophysiology of coronary artery disease (CAD). Cardiovascular protection by SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1Ra) is associated with reduced inflammatory burden but underlying cellular mechanisms remain incompletely defined. We investigated whether SGLT2i and GLP-1Ra synergistically suppress monocyte activation and prevent both systemic inflammatory mediator-induced and monocyte-driven endothelial dysfunction in CAD. METHODS AND

resultsPlasma and circulating monocytes were analyzed in healthy individuals (n = 20), patients with cardiovascular disease without CAD (n = 20), and patients with stable CAD (n = 55), and their effects on endothelial cell responses were assessed. CAD plasma showed increased IL-1β, IL-6, TNF-α, MCP-1, soluble ICAM-1, and VCAM-1, and a proteomic profile enriched in complement, innate immune, and extracellular matrix remodeling pathways. CAD plasma induced oxidative stress in endothelial cells, reduced nitric oxide, increased leukocyte and platelet adhesion, and enhanced procoagulant activity, correlating with circulating TNF-α and sICAM-1. CAD monocytes exhibited a metabolically activated phenotype with increased oxidative stress, mitochondrial activity, glucose and cholesterol uptake, calcium signaling, procoagulant activity, and adhesion to endothelial cells. These changes correlated with circulating TNF-α, sICAM-1, and plasma-induced endothelial dysfunction. CAD monocytes showed increased NF-κB, NOX2, and NLRP3 signaling with reduced CREB/NRF2 pathways, produced elevated levels of pro-inflammatory cytokines, while CAD monocytes-conditioned medium induced endothelial oxidative stress and blunted nitric oxide production. GLP-1Ra or SGLT2i attenuated these effects, while combined treatment provided synergistic protection, reducing CAD plasma-induced endothelial oxidative stress (~ 80%) and restoring endothelial function, reducing CAD monocytes oxidative stress (~ 82%), metabolic activation and pro-thrombotic activity, reprogramming monocytes toward anti-inflammatory phenotype and preventing CAD monocytes-induced endothelial dysfunction.

conclusionCAD features systemic inflammation that drives monocyte activation and endothelial dysfunction. Combined SGLT2i and GLP-1Ra synergistically suppress monocyte pro-inflammatory and pro-thrombotic activity and subsequently driven endothelial dysfunction.