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 β-catenin. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) and adult mouse cardiomyocytes treated with high glucose or Wnt3a (a β-catenin activator). There was no significant change in β-catenin mRNA levels in cardiac tissues or NRCMs. MTZ-mediated β-catenin downregulation was recovered by MG132, a proteasome inhibitor. Immunoprecipitation and immunofluorescence analyses showed augmentation of AXIN1–β-catenin interaction by MTZ in T1DM hearts and in NRCMs treated with Wnt3a; thus, MTZ may potentiate AXIN1–β-catenin linkage to increase β-catenin degradation. Overall, MTZ may alleviate cardiac hypertrophy by mediating AXIN1–β-catenin interaction to promote degradation and inhibition of β-catenin activity. These findings may help inform novel therapeutic strategy to prevent heart failure in patients with diabetes.
X.C., Y. Li, X.Y., and W.Y. contributed equally to this work.
This article contains supplementary material online at https://doi.org/10.2337/figshare.17430266.