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

ABSTRACT 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.