Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, 325000, China.
Wenzhou Medical University, Wenzhou, 325000, China.
Acta Pharmacol Sin. 2024 Sep;45(9):1861-1878. doi: 10.1038/s41401-024-01286-9. Epub 2024 May 8.
Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.
肺动脉高压（PH）是一种无法治愈的进行性致命疾病。坎格列净（CANA）是一种新型糖尿病药物，已被发现具有显著的心血管益处。然而，很少有研究涉及 CANA 在治疗 PH 中的作用和药理机制。因此，我们的研究旨在探讨 CANA 在治疗 PH 中的作用和药理机制。首先，CANA 抑制了小鼠和大鼠 PH 模型中肺动脉压升高、右心室肥厚和血管重构。网络药理学、转录组学和生物学结果表明，CANA 可以通过抑制过度氧化应激和肺动脉平滑肌细胞增殖来改善 PH，部分是通过激活 PPARγ。进一步的研究表明，CANA 抑制了 PPARγ 在 Ser225 的磷酸化（PPARγ 的一个新的丝氨酸磷酸化位点），从而促进了 PPARγ 的核转位，并增加了其抵抗氧化应激和增殖的能力。总之，我们的研究不仅强调了 CANA 对 PH 的潜在药理作用，还揭示了 CANA 诱导的 PPARγ Ser225 磷酸化抑制增加了其抵抗氧化应激和抑制增殖的能力。这些发现可能会激发进一步的研究，并鼓励未来的临床试验探索 CANA 在 PH 治疗中的治疗潜力。
