Methazolamide Attenuates the Development of Diabetic Cardiomyopathy by Promoting β-Catenin Degradation in Type 1 Diabetic Mice
Methazolamide Attenuates the Development of Diabetic Cardiomyopathy by Promoting β-Catenin Degradation in Type 1 Diabetic Mice
复制标题
Methazolamide 通过促进 1 型糖尿病小鼠中 β-Catenin 降解来减轻糖尿病心肌病的发展
DOI：
10.2337/db21-0506
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发表时间：
2022-04-01
期刊：
影响因子：
7.7
通讯作者：
Hou, Ning
中科院分区：
文献类型：
--
作者：
Chen, Xiaoqing;Li, Yilang;Hou, Ning
甲唑胺(MTZ)是一种碳酸酐酶抑制剂，已被证明在2型糖尿病患者和糖尿病db/db小鼠中可以抑制心肌细胞肥大并发挥降糖作用。然而，MTZ在糖尿病心肌病的背景下是否具有心脏保护作用尚不清楚。我们观察了甲氨蝶呤对链脲佐菌素诱导的1型糖尿病(T1 DM)小鼠模型的影响。糖尿病小鼠给予MTZ灌胃(每天10、25或50 mg/kg，连续16周)。在糖尿病组，MTZ显著降低随机血糖和空腹血糖水平，并以剂量依赖的方式改善糖耐量。MTZ可改善T1 DM引起的心脏形态和功能障碍的改变。机制分析表明，MTZ可钝化T1 DM诱导的β-连环蛋白表达增强。在高糖或Wnt3a(一种β-连环蛋白激活剂)处理的新生大鼠心肌细胞和成年小鼠心肌细胞中也观察到了类似的结果。心肌组织和NRCM中β-catenin基因表达水平无明显变化。蛋白酶体抑制剂MG132可恢复MTZ介导的β-连环蛋白下调。免疫沉淀和免疫荧光分析表明，MTZ增强了T1 DM心脏和Wnt3a处理的NRCM中AXIN1-β-连环蛋白的相互作用，因此，MTZ可能增强AXIN1-β-连环蛋白的连接，从而增加β-连环蛋白的降解。总体而言，MTZ可能通过介导AXIN1-β-连环蛋白相互作用来促进β-连环蛋白的降解和抑制β-连环蛋白活性，从而减轻心肌肥厚。这些发现可能有助于提供预防糖尿病患者心力衰竭的新治疗策略。
Methazolamide (MTZ), a carbonic anhydrase inhibitor, has been shown to inhibit cardiomyocyte hypertrophy and exert a hypoglycemic effect in patients with type 2 diabetes and diabetic db/db mice. However, whether MTZ has a cardioprotective effect in the setting of diabetic cardiomyopathy is not clear. We investigated the effects of MTZ in a mouse model of streptozotocin-induced type 1 diabetes mellitus (T1DM). Diabetic mice received MTZ by intragastric gavage (10, 25, or 50 mg/kg, daily for 16 weeks). In the diabetic group, MTZ significantly reduced both random and fasting blood glucose levels and improved glucose tolerance in a dose-dependent manner. MTZ ameliorated T1DM-induced changes in cardiac morphology and dysfunction. Mechanistic analysis revealed that MTZ blunted T1DM-induced enhanced expression of beta-catenin. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) and adult mouse cardiomyocytes treated with high glucose or Wnt3a (a beta-catenin activator). There was no significant change in beta-catenin mRNA levels in cardiac tissues or NRCMs. MTZ-mediated beta-catenin downregulation was recovered by MG132, a proteasome inhibitor. Immunoprecipitation and immunofluorescence analyses showed augmentation of AXIN1-beta-catenin interaction by MTZ in T1DM hearts and in NRCMs treated with Wnt3a; thus, MTZ may potentiate AXIN1-beta-catenin linkage to increase beta-catenin degradation. Overall, MTZ may alleviate cardiac hypertrophy by mediating AXIN1-beta-catenin interaction to promote degradation and inhibition of beta-catenin activity. These findings may help inform novel therapeutic strategy to prevent heart failure in patients with diabetes.