La Trobe
1168702_Cohen,C_2021.pdf (5.12 MB)
Download file

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

Download (5.12 MB)
journal contribution
posted on 2021-07-02, 05:29 authored by Charles CohenCharles Cohen, MJ De Blasio, MKS Lee, GE Farrugia, D Prakoso, Crisdion KrstevskiCrisdion Krstevski, M Deo, DG Donner, H Kiriazis, MC Flynn, Taylah GaynorTaylah Gaynor, Andrew MurphyAndrew Murphy, Grant DrummondGrant Drummond, Ruvantha PintoRuvantha Pinto, Rebecca RitchieRebecca Ritchie
Background: Diabetes 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. Methods: Diabetes 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. Results: Mice 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. Conclusions: Murine 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.


CDC, CK and TLG are supported by the La Trobe University Postgraduate Research Scholarship (LTUPRS), Research Training Program Fees Off-set (RTP-Fo) Scholarship. CDC is supported by a Baker Institute 'Bright Sparks' Scholarship. TLG is supported by Defence Science Institute (DSI) RhD Grant. This work was supported by a project grant to RHR and MJD from the National Health and Medical Research Council (NHMRC) of Australia (APP1158013), and an NHMRC fellowship to RHR (APP1059960) and in part by an infrastructure grant from the Victorian Government of Australia. This work was also supported by an NHMRC Ideas Grant (GNT1188503) to ARP.


Publication Date



Cardiovascular Diabetology



Article Number








Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

Usage metrics