Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

Cheng Chih Chung, Yung Kuo Lin, Yao Chang Chen, Yu Hsun Kao, Yung Hsin Yeh, Nguyen Ngoc Trang, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Background: The novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms. Methods and results: Migration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca2+ fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca2+ leakage, Ca2+ entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na+-H+ exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca2+ leakage, Ca2+ entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. Conclusions: By inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca2+ release, extracellular Ca2+ entry and the profibrotic activities of atrial fibroblasts.

Original languageEnglish
Article number27
JournalCardiovascular Diabetology
Issue number1
Publication statusPublished - Dec 2023


  • Calcium
  • Empagliflozin
  • Fibroblasts
  • Fibrosis
  • Sodium-glucose co-transporter 2
  • Sodium-Hydrogen exchanger

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cardiology and Cardiovascular Medicine


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