Abstract
Background: Diabetes is associated with a significantly elevated risk of heart failure. However, the precise cellular and molecular protagonists underpinning the development of heart failure in diabetes remains unclear. Moreover, very little is known, of how disparate non-myocyte populations of the heart contribute to diabetic cardiomyopathy. Methodology: To address this gap in knowledge, we conducted single-cell transcriptomic analysis of non-myocytes from heart ventricles of spontaneous type-2 diabetic ( db/db ) male mice. Findings were corroborated by flow cytometry, histology and computational analysis of publically available bulk RNA sequencing datasets from alternative diabetes models. Results: Single-cell transcriptomic analysis of db/db mouse hearts revealed a concerted diabetes-induced cellular response driving cardiac pathological remodelling. We identified diabetes-induced up-regulation of pathways contributing to known features of diabetic cardiomyopathy such as dysregulation of vascular homeostasis and lipid metabolism, as well as augmented inflammation, in cell specific contexts. We also identified unexpected characteristics in the diabetic heart, including impaired protein folding and cellular trafficking within lymphatic vessels. Using flow cytometry and histology, increase in inflammatory cells, such as Ly6C hi monocytes, shifts in macrophage phenotype, and increased abundances of fibroblasts and endocardial cells were confirmed. Finally, integration of single-cell transcriptomic data with publically available bulk-RNA sequencing datasets from alternative diabetes models revealed shared hallmarks of diabetic heart and disease context-dependent features. Conclusions: Together, this work offers a new perspective for understanding the cellular and molecular mediators of diabetes-induced cardiac pathology. Targeting these mediators may offer new therapeutic avenues to address the cardiac complications associated with diabetes.
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