Pretreatment with KGA-2727, a selective SGLT1 inhibitor, is protective against myocardial infarction-induced ventricular remodeling and heart failure in mice
Pretreatment with KGA-2727, a selective SGLT1 inhibitor, is protective against myocardial infarction-induced ventricular remodeling and heart failure in mice
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DOI：
10.1016/j.jphs.2019.11.001
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Hirose, Masamichi
中科院分区：
文献类型：
--
作者：
Sawa, Yohei;Saito, Maki;Hirose, Masamichi
最近的研究表明，钠-葡萄糖协同转运蛋白1（SGLT 1）与人类缺血性心肌病有关。然而，SGLT 1阻断是否对缺血性心肌病有效仍不确定。我们研究了选择性SGLT 1抑制剂KGA-2727对心肌梗死（MI）诱导的缺血性心肌病的影响。为了建立MI，在C57 BL/6 J小鼠中进行左前降支冠状动脉（LAD）结扎，给予或不给予KGA-2727。术后4周，所有小鼠进行了研究，左心室短轴缩短率（LVFS）降低，KGA-2727显着改善LAD结扎MI小鼠的LVFS。与假手术小鼠左心室相比，LAD结扎小鼠左心室的心肌细胞直径和ANP、BNP、b-MHC和IL-18基因表达显著增加，KGA-2727抑制了它们的增加。与假手术小鼠相比，LAD结扎小鼠左心室心肌纤维化和CTGF和MMP-3基因表达上调增加，KGA-2727可降低LAD结扎左心室的心肌纤维化和CTGF和MMP-3基因表达上调。与假手术组相比，LAD结扎组SGLT 1蛋白表达水平显著升高，提示KGA-2727预处理可通过阻断SGLT 1抑制MI诱导的左室重构，有望成为治疗缺血性心肌病的新药物。(C)2019作者由Elsevier B. V.代表日本药理学会制作和主办。
Recent studies demonstrated that sodium-glucose co-transporter 1 (SGLT1) is associated with human ischemic cardiomyopathy. However, whether SGLT1 blockade is effective against ischemic cardiomyopathy is still uncertain. We examined the effects of KGA-2727, a selective SGLT1 inhibitor, on myocardial infarction (MI)-induced ischemic cardiomyopathy.To create MI, left anterior descending coronary artery (LAD) ligation with or without KGA-2727 administration was performed in C57BL/6J mice. Four weeks after the operation, all mice were investigated.Left ventricular fractional shortening (LVFS) was reduced and KGA-2727 significantly improved it in LAD-ligated MI mice. The cardiomyocyte diameter, and ANP, BNP, b-MHC, and IL-18 gene expressions significantly increased in LAD-ligated mouse left ventricles compared with those of sham-operated mouse left ventricles, and KGA-2727 inhibited increases in them. Myocardial fibrosis and upregulation of CTGF and MMP-3 gene expressions in the left ventricle were increased in LAD-ligated mice compared with sham-operated mice, and KGA-2727 decreased them in the LAD-ligated left ventricles. SGLT1 protein expression level was significantly higher in LAD-ligated compared with sham-operated mouse ventricles regardless of KGA-2727 treatment.These results suggest that KGA-2727 pretreatment protects against MI-induced left ventricular remodeling through SGLT1 blockade and that it may become a new pharmacological therapy for ischemia-induced cardiomyopathy. (C) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.