Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:127 |
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| Enthalten in: |
Metabolism: clinical and experimental - 127(2022) vom: 10. Feb., Seite 154936 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marfella, Raffaele [VerfasserIn] |
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| Links: |
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| Themen: |
Clinical Trial |
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| Anmerkungen: |
Date Completed 22.02.2022 Date Revised 22.02.2022 published: Print-Electronic ClinicalTrials.gov: NCT03546062 Citation Status MEDLINE |
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| doi: |
10.1016/j.metabol.2021.154936 |
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| 245 | 1 | 0 | |a Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts |
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| 500 | |a Date Completed 22.02.2022 | ||
| 500 | |a Date Revised 22.02.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03546062 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Diabetic cardiomyopathy | |
| 650 | 4 | |a JunD | |
| 650 | 4 | |a SGLT2i | |
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| 650 | 7 | |a Proto-Oncogene Proteins c-jun |2 NLM | |
| 650 | 7 | |a Sodium-Glucose Transporter 2 Inhibitors |2 NLM | |
| 700 | 1 | |a D'Onofrio, Nunzia |e verfasserin |4 aut | |
| 700 | 1 | |a Trotta, Maria Consiglia |e verfasserin |4 aut | |
| 700 | 1 | |a Sardu, Celestino |e verfasserin |4 aut | |
| 700 | 1 | |a Scisciola, Lucia |e verfasserin |4 aut | |
| 700 | 1 | |a Amarelli, Cristiano |e verfasserin |4 aut | |
| 700 | 1 | |a Balestrieri, Maria Luisa |e verfasserin |4 aut | |
| 700 | 1 | |a Grimaldi, Vincenzo |e verfasserin |4 aut | |
| 700 | 1 | |a Mansueto, Gelsomina |e verfasserin |4 aut | |
| 700 | 1 | |a Esposito, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a D'Amico, Michele |e verfasserin |4 aut | |
| 700 | 1 | |a Golino, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Signoriello, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a De Feo, Marisa |e verfasserin |4 aut | |
| 700 | 1 | |a Maiello, Ciro |e verfasserin |4 aut | |
| 700 | 1 | |a Napoli, Claudio |e verfasserin |4 aut | |
| 700 | 1 | |a Paolisso, Giuseppe |e verfasserin |4 aut | |
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