Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
J Cardiol. 2023 Apr;81(4):347-355. doi: 10.1016/j.jjcc.2022.10.003. Epub 2022 Oct 14.
Group 2 pulmonary hypertension (PH) represents PH caused by left heart disease (PH-LHD). LHD induces left-sided filling and PH, finally leading to pulmonary vascular remodeling. Tofogliflozin (TOFO) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the treatment of diabetes. Recent studies have shown that SGLT2 inhibitors have beneficial effects on heart failure, but the effects of SGLT2 inhibitors on PH-LHD remain unclear. We hypothesized that TOFO has protective effects against pulmonary vascular remodeling in PH-LHD mice.
We generated two murine models of PH-LHD: a transverse aortic constriction (TAC) model; and a high-fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg/day) for 3 weeks. AKR/J mice were fed HFD and treated with TOFO (3 mg/kg/day) for 20 weeks. We then measured physical data and right ventricular systolic pressure (RVSP) and performed cardiography. Human pulmonary artery smooth muscle cells (PASMCs) were cultured and treated with TOFO.
Mice treated with TOFO demonstrated increased urine glucose levels. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RVSP. HFD increased body weight (BW) and RVSP compared with the normal chow group. TOFO treatment ameliorated increases in BW and RVSP induced by HFD. Moreover, PASMCs treated with TOFO showed suppressed migration.
TOFO treatment ameliorated right heart overload and pulmonary vascular remodeling for PH-LHD models, suggesting that SGLT2 inhibitors are effective for treating PH-LHD.
2 型肺动脉高压（PH）代表由左心疾病（PH-LHD）引起的 PH。左心疾病导致左心充盈和 PH，最终导致肺血管重构。托格列净（TOFO）是一种用于治疗糖尿病的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂。最近的研究表明，SGLT2 抑制剂对心力衰竭有有益作用，但 SGLT2 抑制剂对 PH-LHD 的影响尚不清楚。我们假设 TOFO 对 PH-LHD 小鼠的肺血管重构具有保护作用。
我们建立了两种 PH-LHD 小鼠模型：主动脉缩窄（TAC）模型；和高脂肪饮食（HFD）模型。C57BL/6J 小鼠接受 TAC 并接受 TOFO（3mg/kg/天）治疗 3 周。AKR/J 小鼠喂食 HFD 并接受 TOFO（3mg/kg/天）治疗 20 周。然后测量物理数据和右心室收缩压（RVSP）并进行心脏描记术。培养人肺动脉平滑肌细胞（PASMCs）并用 TOFO 处理。
用 TOFO 治疗的小鼠表现出尿糖水平升高。TAC 诱导左心室肥大并增加 RVSP。TOFO 治疗改善了 RVSP。与正常饲料组相比，HFD 增加了体重（BW）和 RVSP。TOFO 治疗改善了 HFD 引起的 BW 和 RVSP 增加。此外，用 TOFO 处理的 PASMCs显示出迁移抑制。
TOFO 治疗改善了 PH-LHD 模型的右心负荷过重和肺血管重构，表明 SGLT2 抑制剂对治疗 PH-LHD 有效。
