The sodium-glucose co-transporter 2 inhibitor, empagliflozin, attenuates pulmonary vascular remodelling by inhibiting the phosphorylation of PDGF receptor-β

Background and purpose: Pulmonary vascular remodelling is the key pathological feature of pulmonary arterial hypertension (PAH), but treatments targeting this process are lacking. Recent studies suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors, particularly empagliflozin, may improve PAH outcomes, although the underlying mechanisms remain largely unexplored.

Experimental approach: PAH models were induced in Sprague-Dawley rats with monocrotaline or SU5416-hypoxia (SU-Hx), and empagliflozin (10 mg kg^-1 day^-1) or saline was administered orally. At the end point, haemodynamic, electrocardiographic parameters and pulmonary vascular remodelling were evaluated to investigate effects of empagliflozin in vivo. Effects of empagliflozin in vitro, were assessed using PDGF-BB-/hypoxia-induced proliferation and migration assays on human pulmonary arterial smooth muscle cells (PASMCs). Network pharmacology, molecular docking and surface plasmon resonance (SPR) were performed to explore potential mechanism(s) of empagliflozin treatment.

Key results: Empagliflozin improved haemodynamic, electrocardiographic parameters and pulmonary vascular remodelling in monocrotaline-/SU-Hx-induced PAH models. Empagliflozin inhibited PDGF-BB/hypoxia-stimulated proliferation and migration of human PASMCs and arrested cells in the G0/G1 phase in a concentration-dependent manner. Network pharmacology, biological and SPR results suggested that empagliflozin ameliorated PAH by suppressing excessive proliferation and migration of PASMCs, partly through direct binding to TYR-740, GLY-738 and ASP-737 in the tyrosine kinase effector domain of PDGFRβ, inhibiting PDGFRβ phosphorylation and downstream signalling.

Conclusions and implications: The results highlight a novel mechanism underlying the beneficial effects of empagliflozin in PAH, through direct binding to the tyrosine kinase effector domain of PDGFRβ. This interaction inhibits PDGFRβ phosphorylation, offering new insights into therapeutic strategies for PAH.

PDGFRβ; SGLT2 inhibitor; empagliflozin; pulmonary arterial hypertension; pulmonary vascular remodelling.