The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice
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) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellit...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-023-01955-9 |
| _version_ | 1797453995827003392 |
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| author | Yue Gu Elisa Avolio Valeria V Alvino Anita C Thomas Andrew Herman Poppy J Miller Niall Sullivan Ashton Faulkner Paolo Madeddu |
| author_facet | Yue Gu Elisa Avolio Valeria V Alvino Anita C Thomas Andrew Herman Poppy J Miller Niall Sullivan Ashton Faulkner Paolo Madeddu |
| author_sort | Yue Gu |
| collection | DOAJ |
| description | 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) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. 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). Unpaired parametric or non-parametric tests were used to compare two and multiple groups 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 improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart 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. |
| first_indexed | 2024-03-09T15:30:52Z |
| format | Article |
| id | doaj.art-182661119df04ef1b680839919bcac56 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-03-09T15:30:52Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-182661119df04ef1b680839919bcac562023-11-26T12:15:33ZengBMCCardiovascular Diabetology1475-28402023-08-0122111610.1186/s12933-023-01955-9The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic miceYue Gu0Elisa Avolio1Valeria V Alvino2Anita C Thomas3Andrew Herman4Poppy J Miller5Niall Sullivan6Ashton Faulkner7Paolo Madeddu8Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of BristolBristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of BristolBristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of BristolBristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of BristolSchool of Cellular and Molecular Medicine, University of BristolSchool of Cellular and Molecular Medicine, University of BristolUniversity Hospitals Bristol & WestonDepartment of Comparative Biomedical Sciences, Royal Veterinary CollegeBristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of BristolAbstract 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) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. 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). Unpaired parametric or non-parametric tests were used to compare two and multiple groups 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 improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart 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.https://doi.org/10.1186/s12933-023-01955-9Bone marrowCardiac functionDasatinibdb/db mouse modelDiabetic cardiomyopathyBone marrow-mesenchymal stem cells |
| spellingShingle | Yue Gu Elisa Avolio Valeria V Alvino Anita C Thomas Andrew Herman Poppy J Miller Niall Sullivan Ashton Faulkner Paolo Madeddu The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice Cardiovascular Diabetology Bone marrow Cardiac function Dasatinib db/db mouse model Diabetic cardiomyopathy Bone marrow-mesenchymal stem cells |
| title | The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice |
| title_full | The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice |
| title_fullStr | The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice |
| title_full_unstemmed | The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice |
| title_short | The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice |
| title_sort | tyrosine kinase inhibitor dasatinib reduces cardiac steatosis and fibrosis in obese type 2 diabetic mice |
| topic | Bone marrow Cardiac function Dasatinib db/db mouse model Diabetic cardiomyopathy Bone marrow-mesenchymal stem cells |
| url | https://doi.org/10.1186/s12933-023-01955-9 |
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