Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis.

Autor: Adhikari J; Department of Internal Medicine 1, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan., Hirai T; Department of Diabetes and Endocrinology, Kanazawa Medical University, Kahoku District, Ishikawa, Japan., Kawakita E; Department of Internal Medicine 1, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan.; Department of Diabetes and Endocrinology, Kanazawa Medical University, Kahoku District, Ishikawa, Japan., Iwai K; Health Evaluation Center, Kanazawa Medical University Hospital, Kahoku District, Ishikawa, Japan., Koya D; Department of Diabetes and Endocrinology, Kanazawa Medical University, Kahoku District, Ishikawa, Japan.; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Kahoku District, Ishikawa, Japan., Kanasaki K; Department of Internal Medicine 1, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan.; Department of Diabetes and Endocrinology, Kanazawa Medical University, Kahoku District, Ishikawa, Japan.; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Kahoku District, Ishikawa, Japan.
Jazyk: angličtina
Zdroj: Journal of diabetes investigation [J Diabetes Investig] 2023 Jul; Vol. 14 (7), pp. 844-855. Date of Electronic Publication: 2023 Apr 24.
DOI: 10.1111/jdi.14017
Abstrakt: Aims/introduction: Linagliptin is a selective dipeptidyl peptidase (DPP)-4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP-4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP-4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated.
Materials and Methods: We combined laboratory-based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin-induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out.
Results: Mice with streptozotocin-induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial-mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes-associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9-necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis-associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain-like protein.
Conclusions: Linagliptin showed excellent heart protection in mice with streptozotocin-induced diabetes associated with alterations in human disease-relevant hub genes. Further investigation is required to determine why DPP-4 inhibitors do not show similar superior organ-protective effects in the clinical setting.
(© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
Databáze: MEDLINE
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