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

• Published in: Metabolism, clinical and experimental Vol. 127; p. 154936
• Main Authors: Marfella, Raffaele, D'Onofrio, Nunzia, Trotta, Maria Consiglia, Sardu, Celestino, Scisciola, Lucia, Amarelli, Cristiano, Balestrieri, Maria Luisa, Grimaldi, Vincenzo, Mansueto, Gelsomina, Esposito, Salvatore, D'Amico, Michele, Golino, Paolo, Signoriello, Giuseppe, De Feo, Marisa, Maiello, Ciro, Napoli, Claudio, Paolisso, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2022
• Subjects: 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; Diabetic cardiomyopathy; Female; Follow-Up Studies; Gene Expression - drug effects; Heart - drug effects; Heart - physiology; Heart Transplantation; Humans; JunD; 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; SGLT2i; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; JunD; IRS-2; IRS-1; IVS; HIF-1α; AP-1; HTX; ISHLT; HOMA-IR; DSA; RT-PCR; Diabetic cardiomyopathy; EMB; ALCOA; SGLT2i; PPAR-γ
• DOI: 10.1016/j.metabol.2021.154936
• ISSN: 0026-0495; 1532-8600

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. 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. 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. 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. Potential direct myocardial effects of SGLT2i in human diabetic hearts. [Display omitted] •Molecular mechanisms of heart dysfunction are of the utmost importance in patients with diabetes.•JunD/PPAR-γ pathways in the human diabetic heart may be an attractive therapeutic option.•SGLT2i reduces JunD/PPAR-γ pathway activity to improve heart function in patients with diabetes.