Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts

Metabolism. 2022 Feb:127:154936. doi: 10.1016/j.metabol.2021.154936. Epub 2021 Nov 18.

Abstract

Background: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment.

Methods: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX.

Results: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment.

Conclusion: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Trial registration: ClinicalTrials.gov NCT03546062.

Keywords: Diabetic cardiomyopathy; JunD; SGLT2i.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biopsy
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / surgery
  • Diabetic Cardiomyopathies* / drug therapy
  • Diabetic Cardiomyopathies* / genetics
  • Diabetic Cardiomyopathies* / physiopathology
  • Diabetic Cardiomyopathies* / surgery
  • Female
  • Follow-Up Studies
  • Gene Expression / drug effects
  • Heart / drug effects*
  • Heart / physiology
  • Heart Transplantation
  • Humans
  • Lipid Metabolism / drug effects
  • Male
  • Middle Aged
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Proto-Oncogene Proteins c-jun / genetics*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use

Substances

  • JunD protein, human
  • Proto-Oncogene Proteins c-jun
  • Sodium-Glucose Transporter 2 Inhibitors

Associated data

  • ClinicalTrials.gov/NCT03546062