Methazolamide Attenuates the Development of Diabetic Cardiomyopathy by Promoting β-Catenin Degradation in Type 1 Diabetic Mice
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posted on 2022-01-18, 17:51 authored by Xiaoqing Chen, Yilang Li, Xun Yuan, Wenchang Yuan, Conglin Li, Yue Zeng, Yuling Lian, Xiaoxia Qiu, Yuan Qin, Guiping Zhang, Xia-Wen Liu, Chengfeng Luo, Jiandong Luo, Ning HouMethazolamide
(MTZ), a carbonic anhydrase inhibitor, has been shown to inhibit cardiomyocyte
hypertrophy and exert a hypoglycemic effect in patients with type 2 diabetes
mellitus 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 mellitus.
Funding
This work was supported in part by grants from the National Natural Science Foundation of China (No. 81773720, and No. 81872869), from Natural Science Foundation of Guangdong Province, China (Grant No.2019A1515011848) and from High-level University Construction Fund of Guangdong Province (Grant No. 06-410-2107206).
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