Late Breaking Abstract - SGLT2 promotes endothelial dysfunction and inflammation induced by plasma from patients with pulmonary hypertension

<bold>Background:</bold> Endothelial dysfunction characterized by NO/ROS imbalance is a major driver for pulmonary hypertension (PH). Sodium-glucose co-transporter2 (SGLT2) induction by NADPH oxidases is a novel perpetuator of endothelial ROS. <bold>Objective:</bold> Evaluate the impact of PH plasma on endothelial function and characterize active mediators and role of SGLT2. <bold>Methodology:</bold> Human microvascular and porcine coronary artery endothelial cells (ECs), and porcine pulmonary artery (PA) and lung specimens were exposed to plasma from PAH patients (2022 ESC/ERS score ≥ 3, n=17; ≤ 2, n=13), group 3 PH (n=7) or healthy subjects (n=13). Protein levels were assessed by Western blot and immunofluorescence, ROS by dihydroethidium, and NO by DAF-FM. <bold>Results:</bold> PH plasma increased ROS levels in relation to disease severity whereas healthy subject plasma was inactive. Group 3 PH plasma induced similar effects. SGLT2 inhibitor treatment as well as inhibition of IL-1β, IL-6, TNF-α, ETA, AT1R or NADPH oxidases prevented ROS generation by PH plasma associated with blunted bradykinin-stimulated NO formation. In PA, SGLT2 inhibition and antioxidant treatment prevented ROS formation, induction of SGLT2, NADPH oxidase NOX2, VCAM-1 and TGF-β1, and down-regulation of endothelial NO synthase in response to PH plasma. SGLT2 and NADPH oxidases were also upregulated in lungs and hearts from PH animal models. <bold>Conclusion:</bold> PH plasma caused endothelial dysfunction promoted by SGLT2 and NADPH oxidases and mediated by pro-inflammatory cytokines, ET-1 and Ang II. Thus, SGLT2 appears as a promising target to mitigate excessive vasoconstriction and remodeling following endothelial dysfunction in PH.