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Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition

Authors
  • Cohen, Charles D.1, 2, 3
  • De Blasio, Miles J.1
  • Lee, Man K. S.4
  • Farrugia, Gabriella E.2
  • Prakoso, Darnel1
  • Krstevski, Crisdion2, 3
  • Deo, Minh1
  • Donner, Daniel G.4, 5
  • Kiriazis, Helen4, 5
  • Flynn, Michelle C.4
  • Gaynor, Taylah L.2, 3
  • Murphy, Andrew J.4
  • Drummond, Grant R.3
  • Pinto, Alexander R.2, 3
  • Ritchie, Rebecca H.1, 3
  • 1 Monash Institute of Pharmaceutical Sciences, 399 Royal Parade, Parkville, VIC, 3052, Australia , Parkville (Australia)
  • 2 Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia , Melbourne (Australia)
  • 3 La Trobe University, Bundoora, VIC, Australia , Bundoora (Australia)
  • 4 Baker Heart and Diabetes Institute, Prahran, VIC, Australia , Prahran (Australia)
  • 5 Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, 3010, Australia , Parkville (Australia)
Type
Published Article
Journal
Cardiovascular Diabetology
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jun 01, 2021
Volume
20
Issue
1
Identifiers
DOI: 10.1186/s12933-021-01303-9
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundDiabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart.MethodsDiabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice.ResultsMice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e’:a’ ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6Chi monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice.ConclusionsMurine diabetes results in distinct changes in cardiac cellularity. These changes—in particular increased levels of fibroblasts—offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.

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