Canagliflozin alleviates pulmonary hypertension partially by inhibition of PPARγ S225 phosphorylation and PPARγ-mediated suppression of oxidative stress

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a new anti-diabetic agent, has been found to have remarkable cardiovascular benefits. However, it remains unknown whether CANA is beneficial in vascular pathology of PH. Therefore, our study aims to investigate the role and pharmacological mechanism of CANA in treating PH. Firstly, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Then, network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH through suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially by activation of PPARγ. Further studies demonstrated that CANA inhibited PPARγ Ser225 phosphorylation (a novel serine phosphorylation in PPARγ), thereby promoting nuclear translocation of PPARγ, enhancing its ability to resist oxidative stress and proliferative. Taken together, this study is the first to uncover the potential pharmacological effect and molecular mechanisms of CANA on PH, aiming to encourage future research and clinical trials.