2. Academic Validation
  3. Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

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

  • Cardiovasc Diabetol. 2023 Feb 6;22(1):27. doi: 10.1186/s12933-023-01756-0.
Cheng-Chih Chung 1 2 3,  Yung-Kuo Lin 1 2 3,  Yao-Chang Chen 4,  Yu-Hsun Kao 5 6,  Yung-Hsin Yeh 7 8,  Nguyen Ngoc Trang 9,  Yi-Jen Chen 10 11 12 13
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 3 Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
  • 5 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan. [email protected].
  • 6 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 7 Division of Cardiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 8 College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 9 Radiology Center, Bach Mai Hospital, Hanoi, Vietnam.
  • 10 Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 11 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 12 Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 13 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan. [email protected].
PMID: 36747205 DOI: 10.1186/s12933-023-01756-0
Abstract

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.

Keywords

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

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