Tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, improves pulmonary vascular remodeling due to left heart disease in mice
Tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, improves pulmonary vascular remodeling due to left heart disease in mice
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DOI：
10.1016/j.jjcc.2022.10.003
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发表时间：
2023-02-16
影响因子：
2.5
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
--
作者：
Joki, Yusuke;Konishi, Hakuoh;Minamino, Tohru
背景：第2组肺动脉高压（PH）代表由左心脏病引起的PH（PH-LHD）。LHD引起左侧充盈和PH，最终导致肺血管重构。Tofoglivaline（TOFO）是一种钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂，用于治疗糖尿病。最近的研究表明，SGLT 2抑制剂对心力衰竭具有有益作用，但SGLT 2抑制剂对PH-LHD的影响尚不清楚。我们假设TOFO对PH-LHD小鼠肺血管重构具有保护作用。方法：我们建立了两种PH-LHD小鼠模型：横向主动脉缩窄（TAC）模型和高脂饮食（HFD）模型。对C57 BL/6 J小鼠进行TAC并用TOFO（3 mg/kg/天）处理3周。给AKR/J小鼠喂食HFD，并用TOFO（3 mg/kg/天）处理20周。然后我们测量了物理数据和右心室收缩压（RVSP），并进行心电图。培养人肺动脉平滑肌细胞（PASMCs），用TOFO处理。结果：用TOFO处理的小鼠表现出尿糖水平增加。TAC可引起左心室肥厚和RVSP增加。TOFO治疗可改善RVSP。高脂饮食组大鼠体重和RVSP增加，与正常饲料组相似。TOFO治疗改善了HFD诱导的BW和RVSP增加。此外，用TOFO处理的PASMCs显示出抑制的迁移。结论：TOFO治疗可改善PH-LHD模型的右心超负荷和肺血管重构，表明SGLT 2抑制剂可有效治疗PH-LHD。(c)2022年日本心脏病学院。由爱思唯尔有限公司出版。保留所有权利。
Background: 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. Methods: 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. Results: Mice treated with TOFO demonstrated increased urine glucose levels. TAC induced left ventricular hyper-trophy and increased RVSP. TOFO treatment improved RVSP. HFD increased body weight (BW) and RVSP com-pared with the normal chow group. TOFO treatment ameliorated increases in BW and RVSP induced by HFD. Moreover, PASMCs treated with TOFO showed suppressed migration. Conclusions: TOFO treatment ameliorated right heart overload and pulmonary vascular remodeling for PH-LHD models, suggesting that SGLT2 inhibitors are effective for treating PH-LHD.(c) 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.