Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease in which narrowing of the pulmonary vasculature often leads to right ventricular (RV) failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, provides well-established clinical benefits for patients with heart failure.

Aims and Objective: To investigate the effects of EMPA in vitro and in vivo.

Methods: Pulmonary microvascular endothelial cells (MVEC) from PAH patients and controls, were treated with 1 ?M EMPA. Sprague-Dawley rats were injected with 25 mg/kg Sugen 5416 followed by 3 weeks of 10% oxygen exposure (SuHx) to induce PAH, and subsequently randomised to 300 mg/kg EMPA (n=12) or placebo (n=12). After 4 weeks of treatment, echocardiography and right heart catheterization (RHC) were performed. The rats were sacrificed for histological evaluation.

Results: In SuHx PAH rats, EMPA attenuated pulmonary vascular resistance (PVR) and pulmonary arterial pressure. EMPA treatment reversed RV dilatation and wall thickening. EMPA reduced RV fibrosis and attenuated vascular occlusion, in particular by reducing intimal thickness. In PAH MVECs, EMPA treatment, and SGLT2 knockdown, increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?), a master regulator of mitochondrial biogenesis. In addition, EMPA attenuated mitochondrial oxidative stress and MVEC proliferation.

Conclusion: Empagliflozin ameliorated pulmonary vascular remodeling and improved right ventricular hemodynamics in a PAH rat model. These effects could be mediated by improvement in mitochondrial biogenesis and attenuation of hyperproliferation.