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Luseogliflozin inhibits high glucose-induced TGF-β2 expression in mouse cardiomyocytes by suppressing NHE-1 activity

Naoya Osaka1, Yusaku Mori2, Michishige Terasaki1

  • 1Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo, Japan.

The Journal of International Medical Research
|May 5, 2022
PubMed
Abstract

Insights

Sodium-glucose cotransporter-2 (SGLT2) inhibitors like luseogliflozin may protect the heart in diabetes. This study shows luseogliflozin reduces cardiac hypertrophy by suppressing sodium-hydrogen exchanger-1 (NHE-1) activity and transforming growth factor-beta 2 (TGF-β2) expression.

Area of Science:

  • Cardiovascular Research
  • Metabolic Diseases
  • Molecular Biology

Background:

  • Sodium-glucose cotransporter-2 (SGLT2) inhibitors demonstrate cardioprotective effects in diabetic patients.
  • The precise molecular mechanisms underlying SGLT2 inhibitor cardioprotection, especially given SGLT2's absence in cardiac tissue, remain unclear.
  • Investigating the role of sodium-hydrogen exchanger-1 (NHE-1) activity in high glucose-induced cardiac dysfunction is crucial.

Purpose of the Study:

  • To determine if the SGLT2 inhibitor luseogliflozin mitigates high glucose-induced damage in cardiomyocytes.
  • To elucidate the potential role of suppressing sodium-hydrogen exchanger-1 (NHE-1) activity in mediating luseogliflozin's cardioprotective effects.
  • To examine the impact of luseogliflozin on cardiac hypertrophy and fibrosis in a diabetic mouse model.

Main Methods:

  • Cardiomyocytes were exposed to normal or high glucose conditions, treated with vehicle, luseogliflozin, or the NHE-1 inhibitor cariporide.
  • NHE-1 activity was assessed using the SNARF assay, and gene expression was analyzed via real-time RT-PCR.
  • Cardiac hypertrophy, fibrosis, and related molecular markers (TGF-β2) were evaluated in luseogliflozin-treated db/db mice.

Main Results:

  • High glucose elevated NHE-1 activity and transforming growth factor-beta 2 (TGF-β2) mRNA in cardiomyocytes.
  • Luseogliflozin and cariporide individually inhibited these high glucose-induced changes, with no additive effect observed for TGF-β2 mRNA when combined.
  • Luseogliflozin treatment in db/db mice reduced cardiac hypertrophy and fibrosis, correlating with decreased cardiac TGF-β2 expression.

Conclusions:

  • Luseogliflozin may exert cardioprotective effects in diabetes by inhibiting NHE-1 activity.
  • This inhibition of NHE-1 activity by luseogliflozin appears to reduce TGF-β2 expression in cardiomyocytes.
  • The suppression of TGF-β2 expression is a potential mechanism through which luseogliflozin mitigates cardiac hypertrophy in diabetic conditions.
Keywords:
Cariporidediabetic cardiomyopathyfibrosisluseogliflozinsodium-glucose cotransporter-2 inhibitorsodium-hydrogen exchanger-1transforming growth factor-β2

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