Abstract
Background: Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs), clinically used as an anti-cancer treatment, influence glucose and lipid metabolism, leading to improved glycemic control and allowing insulin discontinuation in cancer patients with diabetes mellitus. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.
Methods: Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Two-tailed independent samples t-tests and one-way analysis of variance were used as appropriate.
Results: Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with an improvement in the diastolic index E/A. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart and BM, and lower circulating PAI-1, compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.
Conclusions: Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.
Methods: Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Two-tailed independent samples t-tests and one-way analysis of variance were used as appropriate.
Results: Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with an improvement in the diastolic index E/A. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart and BM, and lower circulating PAI-1, compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.
Conclusions: Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.
| Original language | English |
|---|---|
| Article number | 214 |
| Number of pages | 16 |
| Journal | Cardiovascular Diabetology |
| Volume | 22 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 17 Aug 2023 |
Bibliographical note
Funding Information:This study was supported by China Scholarship Council–University of Bristol joint-funded PhD Scholarship (Support No. 201906250207) (to YG).
Funding Information:
The Authors would like to acknowledge Miss Hannah Martin, from the University of Bristol, for the technical help with the processing of mouse histological samples and Mr Tom Hathway, from the University of Bristol, for the technical help with multiplex assay. They are also grateful to Dr Gallia Graiani, from the University of Parma (Italy), for sharing advice to improve the immunohistochemistry staining of mouse bone marrow samples, and Dr Marianna Santopaolo, from the University of Bristol, for sharing the protocol for human and mouse bone marrow cells isolation. We also wish to acknowledge the following facilities of the University of Bristol: the Wolfson Bioimaging Facility for providing training and access to confocal microscopes, and the Histology Facility for the mouse bone marrow tissue sectioning and expert technical advice. Drawings were created with Biorender.com.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
Keywords
- diabetes mellitus
- Diabetic Cardiomyopathy
- Dasatinib
- cardiac steatosis
- senolytic agent
- db/db mouse model
