Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signalling pathway in diabetic cardiomyopathy.

Autor:	Madonna R; Cardiology Division, Department of Pathology, University of Pisa, Via Paradisa, 56124 Pisa, Italy., Moscato S; Histology Division, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy., Cufaro MC; Department of Pharmacy, 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy.; Analytical Biochemistry and Proteomics Laboratory, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy., Pieragostino D; Analytical Biochemistry and Proteomics Laboratory, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy.; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy., Mattii L; Histology Division, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy., Del Boccio P; Department of Pharmacy, 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy.; Analytical Biochemistry and Proteomics Laboratory, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Via Colle dell'Ara, 56100 Chieti, Italy., Ghelardoni S; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Via Savi 10, 56126 Pisa, Italy., Zucchi R; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Via Savi 10, 56126 Pisa, Italy., De Caterina R; Cardiology Division, Department of Pathology, University of Pisa, Via Paradisa, 56124 Pisa, Italy.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 May 22; Vol. 119 (5), pp. 1175-1189.
DOI:	10.1093/cvr/cvad009
Abstrakt:	Aims: Sodium-glucose cotransporter 2 inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and non-diabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy. Methods and Results: Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day), had fewer apoptotic cells (4.9 ± 2.1 vs. 1 ± 0.5 TUNEL-positive cells %, P < 0.05), less senescence (10.1 ± 2 vs. 7.9 ± 1.2 β-gal positivity/tissue area, P < 0.05), fibrosis (0.2 ± 0.05 vs. 0.15 ± 0.06, P < 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs. 2.3 ± 0.6 fluorescence intensity/total area, P < 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a down-regulation of the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to the modulation of cardiomyogenic transcription factors, we analysed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice [0.5 ± 0.01 densitometric units (DU)], non-diabetic mice treated with EMPA (2.2 ± 0.01 DU, P < 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, P < 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs. 2.2 ± 0.01 target protein/β-actin ratio, P < 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer glycogen synthase kinase 3 beta (GSK3β), leading to reactivation of cardiomyogenic transcription factors. Conclusion: Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signalling pathway in the context of diabetes. Competing Interests: Conflict of interest: The authors declare that the research was conducted in the absence of any conflict of interest. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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