Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts
Raffaele Marfella, Nunzia D'Onofrio, Maria Consiglia Trotta, Celestino Sardu, Lucia Scisciola, Cristiano Amarelli, Maria Luisa Balestrieri, Vincenzo Grimaldi, Gelsomina Mansueto, Salvatore Esposito, Michele D'Amico, Paolo Golino, Giuseppe Signoriello, Marisa De Feo, Ciro Maiello, Claudio Napoli, Giuseppe Paolisso, Raffaele Marfella, Nunzia D'Onofrio, Maria Consiglia Trotta, Celestino Sardu, Lucia Scisciola, Cristiano Amarelli, Maria Luisa Balestrieri, Vincenzo Grimaldi, Gelsomina Mansueto, Salvatore Esposito, Michele D'Amico, Paolo Golino, Giuseppe Signoriello, Marisa De Feo, Ciro Maiello, Claudio Napoli, Giuseppe Paolisso
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.
Conflict of interest statement
Declaration of competing interest The authors declare that they have no conflict of interest.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Source: PubMed